Thermal sensing with bridge circuitry

ABSTRACT

Thermal sensing devices can include two subsets of thermal sensors connected in a bridge by circuitry on the same support layer or surface with the sensors. Each thermal sensor can be formed in a patterned layer of semiconductor material, and the bridge circuitry can include leads formed in a patterned layer of conductive material, over or under the semiconductor layer. In one implementation, the bridge circuitry includes conductive portions that extend across and electrically contact the lower surface of each sensor&#39;s semiconductor slab. The bridge circuitry can also include pads that can be electrically contacted, such as by pogo pins. The device&#39;s reaction surface can be spaced apart from or over the thermal sensors. The device&#39;s components can be shaped and positioned so that the bridge&#39;s offset voltage is below the sensitivity level required for an application, such as by left-right symmetry about an axis.

RELATED APPLICATIONS

This application is a continuation-in-part of pending U.S. patentapplication Ser. No. 10/114,611 (U.S. Patent Application Publication No.2003/0186453) (“the parent application”), which is incorporated hereinby reference in its entirety. Other continuations-in-part of the parentapplication include U.S. patent application Ser. No. 10/303,446 (U.S.Patent Application Publication No. 2003/0186454) and Ser. No. 10/303,500(U.S. Patent Application Publication No. 2003/0186455), both of whichare incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates generally to techniques that sense thermalstimuli. In particular, implementations employ thermometer elements orother thermal sensors connected by bridge circuitry into a bridge. Suchbridges can be used, for example, in a calorimeter, a term used hereinto refer to any device or apparatus that measures quantities of absorbedor evolved heat or determines specific heats; the use of a calorimeteris referred to herein as calorimetry.

Calorimetry can measure enthalpic changes, including enthalpic changesarising from reactions, phase changes, changes in molecularconformation, temperature variations, and other variations of interestthat may occur for a particular specimen. By measuring enthalpic changesover a series of conditions, other thermodynamic variables may bededuced. For example, measurements of enthalpy as a function oftemperature reveal the heat capacity of a specimen, and titrations ofreacting components can be used to deduce the binding constant andeffective stoichiometry for a reaction.

It is known to use bridges in calorimetry and other thermal sensingapplications. For example, U.S. Pat. No. 3,467,501 describes amicrocalorimeter in which a cell includes measuring thermistors mountedin a solid reactant zone and reference thermistors mounted in a blocksurrounding the cell; the resistances of the thermistors may be comparedby connecting them into a Wheatstone bridge. U.S. Pat. Nos. 4,298,392;5,312,587; 5,265,417; 5,451,371; and 6,701,774 describe other techniquesin which thermistors, other temperature sensitive resistors, or othertemperature sensing elements are in a Wheatstone bridge.

Previous techniques in thermal sensing with bridges have a number oflimitations. It would be advantageous to have additional techniques forbridges that include thermometer elements or other thermal sensors. Inparticular, it would be advantageous to have techniques that could beused in very sensitive calorimetry.

SUMMARY OF THE INVENTION

The invention provides various exemplary embodiments, including devices,arrays, and methods. In general, each embodiment involves thermometerelements or other thermal sensors connected in a bridge.

These and other features and advantages of exemplary embodiments of theinvention are described below with reference to the accompanyingdrawings, in which like reference numerals refer to components that arealike or similar in structure or function.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic plan view depicting components of a firstnanocalorimeter implementation.

FIG. 2 is a schematic plan view depicting components of a secondnanocalorimeter implementation.

FIG. 3 is a schematic plan view depicting components of a thirdnanocalorimeter implementation.

FIG. 4 is a schematic plan view depicting components of a fourthnanocalorimeter implementation.

FIG. 5 is a schematic circuit diagram of a first electronic measuringsystem with resistive thermometer elements.

FIG. 6 is a schematic cross-section showing merging of deposited dropson a nanocalorimeter, such as in one of FIGS. 1-4.

FIG. 7 is a schematic diagram of a second electronic measuring system.

FIG. 8 is a top plan view of an array of components of a nanocalorimeterthat can be used with the system of FIG. 7.

FIG. 9 is a cross-sectional diagram illustrating the operatingenvironment of a nanocalorimeter as in FIG. 8.

FIG. 10 is a cross-sectional diagram illustrating an implementation ofprocess flow of a nanocalorimeter as in FIG. 8.

FIG. 11 is a schematic diagram of a third electronic measuring systemthat includes resistive thermal sensors.

FIG. 12 is a top plan view of a pair of low noise resistive thermalsensors that can be used in the system of FIG. 11.

FIG. 13 is a cross section of the pair of thermal sensors, taken alongline 13-13 in FIG. 12.

FIG. 14 is a partially schematic top view of a thermal sensing cell thatincludes two pairs of thermal sensors like those of FIGS. 12 and 13.

FIG. 15 shows a sequence of cross-sectional views in production of athermal sensing cell, taken along line 15-15 in FIGS. 12 and 14.

FIG. 16 is a schematic layout diagram of an integrated circuit thatincludes an array of thermal sensing cells like that shown in FIG. 14.

FIG. 17 is a cross section of a pair of thermal sensors along the sameline as FIG. 13 but in an alternative implementation with layers in adifferent order.

FIG. 18 is a cross section similar to FIGS. 13 and 17, for animplementation in which semiconductor slabs function both as thermalsensors and drop merging electrodes.

FIG. 19 is a cross section as in FIG. 18 for an implementation without athermally conductive component.

FIG. 20 is a flow chart showing operations in performing calorimetrywith an array as in FIG. 16, implemented with cells as in any of FIGS.12-15, 17, 18, or 19.

DETAILED DESCRIPTION

The below-described implementations can be applied in measuring thermaleffects of chemical reactions as well as in various other ways, some ofwhich are described in the parent application, incorporated herein byreference. In describing some implementations, the terms “targetmolecule”, “ligand”, “test ligand”, “target protein”, and other termsare used herein with substantially the same meanings as set forth in theparent application.

As used herein, the term “thermal change” encompasses the release ofenergy in the form of heat or the absorption of energy in the form ofheat.

As used herein, a “nanocalorimeter” is a calorimeter capable ofmeasuring in the range of nanocalories. Exemplary implementations of thepresent invention can be applied generally in calorimeters andcalorimeter arrays. More specifically, implementations can be applied innanocalorimeters and nanocalorimeter arrays that enable measurement ofenthalpic changes, such as enthalpic changes arising from reactions,phase changes, changes in molecular conformation, and the like.Furthermore, combinatorial methods and high-throughput screening methodscan use such nanocalorimeters in the study, discovery, and developmentof new compounds, materials, chemistries, and chemical processes, aswell as high-throughput monitoring of compounds or materials, orhigh-throughput monitoring of the processes used to synthesize or modifycompounds or materials.

Compounds or materials can be identified by the above methods and theirtherapeutic uses (for diagnostic, preventive or treatment purposes),uses in purification and separation methods, and uses related to theirnovel physical or chemical properties can then be determined. The parentapplication, incorporated herein by reference, describes use ofhigh-throughput screening methods and other such techniques in variousapplications.

Various techniques have been developed for producing structures with oneor more dimensions smaller than 1 mm. In particular, some techniques forproducing such structures are referred to as “microfabrication.”Examples of microfabrication include various techniques for depositingmaterials such as growth of epitaxial material, sputter deposition,evaporation techniques, plating techniques, spin coating, and other suchtechniques; techniques for patterning materials, such as etching orotherwise removing exposed regions of thin films through aphotolithographically patterned resist layer or other patterned layer;techniques for polishing, planarizing, or otherwise modifying exposedsurfaces of materials; and so forth.

In general, the structures, elements, and components described hereinare supported on a “support structure” or “support surface”, which termsare used herein to mean a structure or a structure's surface that cansupport other structures. More specifically, a support structure couldbe a “substrate”, used herein to mean a support structure on a surfaceof which other structures can be formed or attached by microfabricationor similar processes. Also, a support structure could be a “supportlayer”, meaning a layer of material that can support other structures;for example, a support layer could include a polymer film and a barrierlayer on a side of the polymer film.

A structure or component is “directly on” a surface when it is both overand in contact with the surface. A structure is “fabricated on” asurface when the structure was produced on or over the surface bymicrofabrication or similar processes. A process that produces a layeror other accumulation of material over or directly on a substrate'ssurface can be said to “deposit” the material.

The surface of a substrate or other support surface is treated herein asproviding a directional orientation as follows: A direction away fromthe surface is “up”, “over”, or “above”, while a direction toward thesurface is “down”, “under”, or “below”. The terms “upper” and “top” aretypically applied to structures, components, or surfaces disposed awayfrom the surface, while “lower” or “underlying” are applied tostructures, components, or surfaces disposed toward the surface. Ingeneral, it should be understood that the above directional orientationis arbitrary and only for ease of description, and that a supportstructure or substrate may have any appropriate orientation.

FIG. 1 shows a plan view of nanocalorimeter detector 100, a firstimplementation of a detector that can be used in a nanocalorimeterarray. This implementation enables a passive thermal equilibration ofthe combined protein, water, and ligand drops with the device so thatthe resultant temperature changes can be detected by means of atemperature-sensing device. Suitable thermometer elements are based onthin film materials and include various resistive thermometer elements,resistive thermal sensors, thermistors, and so forth, examples of whichare described below.

Because the measurement region is kept small enough and sufficientlythermally conductive, through the use of a thermally conducting layersuch as aluminum or copper, the passive equilibration time will besmall. As used herein, the terms “thermally conducting” or “thermallyconductive” are applicable to any component, layer, or other structurethat sufficiently conducts thermal signals from one position or regionto another that the thermal signals can affect concurrent thermallysensitive operations in the other position or region. For example, ifthe thermal signals include information, the information could beavailable for sensing and electrical detection in the other position orregion. Two components are in “thermal contact” even if not in directcontact if a structure between them is conductive for thermal signals ofinterest. More generally, thermal signals may follow a “thermallyconductive path” between two components, meaning a path along which thesignals are conducted.

The term “sensing” is used herein in the most generic sense of obtaininginformation from a physical stimulus; sensing therefore includes actionssuch as detecting, measuring, and so forth. A “thermal sensor” isaccordingly used herein to refer to an element or combination ofelements that senses at least one thermal stimulus such as heat,temperature, or random kinetic energy of molecules, atoms, or smallercomponents of matter. A “resistive thermal sensor” is a thermal sensorwith electrical resistance that varies with the thermal stimulus that itsenses, in contrast to various thermal sensors that sense in other wayssuch as with thermocouples or thermopiles. The terms “resistivethermometer element” and “resistive thermometer” similarly refer to anelement of any kind with electrical resistance that varies withtemperature. As used herein, the term “thermistor” means an electricallyresistive component that includes semiconductor material with resistancethat varies in response to a thermal change; a thermistor can thereforebe employed in a resistive thermal sensor or a resistive thermometer. Ineach of these definitions, variation in resistance would include bothlinear and non-linear variations; a non-linear variation might occur ina thermistor, for example if a temperature change causes a phase changein the semiconductor material.

Resistive thermal sensors and resistive thermometers can, for example,be made from materials with a high temperature coefficient ofresistivity (TCR) in comparison with those of other materials. Examplesof semiconductor materials with high TCR include amorphous silicon,vanadium oxide (VO_(x)), yttrium barium copper oxide (YBCO), and mercurycadmium telluride. Other materials that have been used in resistivethermal sensors include, for example, platinum, nickel, copper,iron-nickel alloys such as balco, tungsten, iridium, oxides of nickel,manganese, iron, cobalt, copper, magnesium, and titanium, and othermetals, metal alloys, and oxides of metal. Any such material is referredto herein as a “high TCR material”. Furthermore, unless otherwisespecified, the terms “vanadium oxide” and “VO_(x)” refer herein to anyoxide or combination of oxides of vanadium that can be used in thecontext, such as V₂O₅, VO₂, V₂O₃, VO, and so forth.

Nanocalorimeter detector 100 includes thermal isolation layer 110, whichcontains measurement region 160 and reference region 170. Regions 160and 170 may also be contained in separate isolation regions, asdescribed hereinbelow. Thermal isolation layer 110 provides isolationfrom surrounding thermal environments, thus increasing measurement timeand reducing thermal noise, also referred to herein as Johnson noise,i.e. the theoretical minimum achievable noise level. Although layer 110is used in this implementation to thermally isolate the reaction andtemperature sensing components of the nanocalorimeter detector 100, anymeans to thermally isolate these components can be used in alternateimplementations.

As used herein, the terms “thermal isolation” or “thermal isolating” areapplicable to any layer or other structure that sufficiently preventsconduction of or fails to conduct thermal signals from one region toanother, so that the thermal signals do not affect concurrent thermallysensitive operations in the other region. A thin layer, for example, maybe thermally isolating in its lateral directions, i.e. directionsapproximately parallel to its surfaces, but may permit thermalconduction in its thickness direction, i.e. the direction perpendicularto its surfaces.

In this implementation, thermal isolation layer 110 may include aplastic material in thin foil form (typically ranging from less than 15μm to approximately 25 μm in thickness, possibly as thin as 2 μm and asthick as 500 μm for some applications). Candidate plastic materialsinclude polymers such as polyimide (for example DuPont Kapton® andothers), polyester (for example DuPont Mylar®, DuPont Teonex® PEN, orDuPont Teijin® Tetoron® PET) foil, PolyEtherEtherKetone (PEEK), orPolyPhenylene Sulphide (PPS). Alternatively, thermal isolation layer 110includes other thin layers of sufficiently low thermal conductivity,such as SiN and comparable materials.

Measurement region 160 and reference region 170 include thermalequilibrium regions 120 and 125 respectively, that are thermallyisolated from the detector's mechanical support. In this implementation,thermal equilibrium region 120 contains two resistive thermometers 140,which measure the reaction temperature, while thermal equilibrium region125 contains a second set of two resistive thermometers 140, whichmeasure the variations in the background temperature. Resistivethermometers 140 can therefore be produced in thermal equilibriumregions 120 and 125 using microfabrication or other techniques, such asprinted circuit board fabrication techniques.

As used herein, the term “reaction region” refers to a region in which areaction can occur, producing thermal change. A “reaction surface” is apart of a surface that is a reaction region. Both thermal equilibriumregions 120 and 125 are reaction regions and, more specifically,reaction surfaces because they are sufficiently large to receive andsupport separate drops of protein and ligand deposited by directprinting and also to support the combination of these two drops aftermerging, triggered by an example drop merging device 130. For example,for a 400 nl final drop size, the detector, which includes themeasurement and reference regions, may be 3.7 mm by 4.6 mm. Each thermalequilibrium region 120 and 125 has sufficient thermal conduction for theregion to equilibrate quickly relative to thermal dissipation. Theregions each have a sufficiently low heat capacity such that little ofthe heat of reaction is absorbed in the support. High thermalconductivity with low heat capacity may be accomplished, for example,with a metal film such as a 10 μm thick aluminum or copper filmextending over the area of the thermal equilibrium region. In thisexample, for a 400 nl drop and a 10 μm thick aluminum film, the filmabsorbs approximately 7% of the heat of reaction. In general, the term“high thermal conductivity” refers herein to a thermal conductivity thatis approximately as great or greater than those of aluminum and copper.

As suggested above, in this implementation, the thermal equilibriumregions 120 and 125 must be thermally isolated from their environment sothat the temperature difference caused by the reaction takes arelatively long time to dissipate. The longer this dissipation time, thelonger the signal can be integrated during measurement, which improvesthe signal to noise ratio. For example, a 10 second integration timecorresponds to a 0.1 Hz measurement bandwidth and increases the signalto noise ratio by 3.2 over a 1 second integration. Thermal dissipationcan occur through at least four different channels: conduction acrossthe supporting medium, conduction through the electrical interconnect,conduction through the surrounding environment and evaporation. For theexample of conduction across the thermal isolation layer 110, the rateof heat transfer from the drop equals the thermal conductivity of thelayer 110 multiplied by the cross section of the layer 110 through whichthe heat is conducted and the temperature gradient across the region, orQ=ΛAdT/dx,

-   -   where Λ is the thermal conductivity of thermal isolation layer        110, A is the cross section of the region through which the heat        is conducted and dT/dx is the temperature gradient across        thermal isolation layer 110. Note Q=C dT/dt where C is the heat        capacity of the drop, and from this        T=T _(o) e ^(−ΛAt/CL),    -   where t is the time, L is the length of the isolation layer 110,        and all temperatures are relative to the temperature of the        surrounding environment, with the approximation dT/dx=T/L. The        time constant, τ, for thermal dissipation is therefore        τ═CL/ΛA.

Consequently, the time constant increases with increases in the heatcapacity of the drop and decreases with increases in the rate of thermalconduction. Note that while the heat capacity of the drop increases withdrop size, increasing the drop size reduces the density of detectors onan array of detectors, increases the thermal equilibration time for thedrop, and uses valuable material. A lower array density means a largerarray size for a given detector number.

In the example implementation, drop size is 400 nl for the combined dropafter merging. For this drop size, estimates of the time constantsassociated with different dissipation channels in one implementation areshown in the following Table 1: TABLE 1 Time Conduction Channel ConstantConduction across support layer + interconnect leads 110 sec  Conductionthrough vapor (air) 6 sec Evaporation (25° C. operation) 8 sec

For the purposes of Table 1, it was assumed that the thermal isolationlayer is 7 μm thick plastic and there are eleven interconnect leads withthickness of 0.1 μm for each thermal equilibrium region. As mentionedabove, the thermal isolation layer for this example implementation maybe fabricated of a plastic material in thin foil form (typically rangingfrom less than 15 μm to approximately 25 μm in thickness for thisimplementation, possibly as thin as 2 μm and as thick as 500 μm for someapplications), thereby ensuring that the above time constant forconduction across the thermal isolation layer is large compared with themeasurement bandwidth. Examples of candidate plastic materials includepolyimide (for example Dupont Kapton®. and others), polyester (forexample Dupont Mylar®, DuPont Teonex® PEN, or DuPont Teijin® Tetoron®PET) foil, PolyEtherEtherKetone (PEEK), PolyPhenylene Sulphide (PPS),polyethylene, or polypropylene. Rather than air, the vapor could be anyappropriate gas or combination of gasses, such as argon or possiblyxenon.

In the implementation of FIG. 1, the same material may be used for thesupport and the thermal equilibration, including the resistivethermometers. Consequently, one important consideration in selecting asubstrate polymer is the highest temperature that is needed insubsequent deposition and processing of thermometer, conductor andinsulator films in the particular implementation. As an example, thetemperature needed in the deposition of amorphous silicon thermometermaterial is typically in the range of 170-250° C. This requires theselection of a substrate polymer film with a high softening temperature.These polymers may include, but are not limited to, polyimide,PolyEtherEtherKetone (PEEK), or PolyPhenylene Sulphide (PPS).Conversely, deposition of vanadium oxide thermometer material can bedone at a substantially lower temperature such as room temperature. Thisallows the selection of substrate polymers with a lower softening point,such as polyester (Dupont Mylar® or DuPont Teonex® PEN).

These plastic substrates enable low cost manufacturing that can scale tolarge arrays of detectors, which enable fast and cost effective testingof large numbers of reactions. Detectors as in FIG. 1 could be used, forexample, in detector array sizes of 96, 384, 1536 and larger. Thelow-cost detector arrays might also be used once and then discarded,eliminating time-consuming washing steps and reducing problems withcross-contamination.

Another thermal consideration is the characteristic time for a drop toequilibrate with the detector after it is placed on the detector. Thisis a combination of the characteristic time for conduction of heatthrough the drop, t₁, and the characteristic conduction time across thedetector, t₂. In an implementation, an aluminum film is used to increasethe thermal conduction across the detector. An estimate of thecharacteristic time t₁ ist ₁=0.44R ²/α≅0.6 sec,

-   -   where R is the drop radius, in this example 460 μm, and α is the        thermal diffusivity of the drop, 0.0015 cm²/sec for water. For        thin plastic substrates, the characteristic time for lateral        conduction across the detector is governed by conduction across        the metal film incorporated into the design for temperature        equilibration, which is an aluminum strip in this example. An        estimate for this characteristic time is        t ₂=(ρC _(p) V)_(drop) ×L _(Al)/4R _(drop) ×δ×k _(Al)≅0.4 sec,    -   where ρ is the density of the drop, 1 g/cm³ in this example;        C_(P) is the specific heat, 1 cal/gK in this example; L_(Al) is        the length of the conduction path along the aluminum strip from        one drop to the other, 2.5 R_(drop) in this example; δ is the        aluminum strip thickness, 10 μm in this example; and k_(Al) is        the aluminum thermal conductivity, 0.57 cal/K-cm-sec. The        aluminum thickness is selected to provide sufficient thermal        conduction without contributing significantly to the heat        capacity of the detector. Heat capacity of the detector must be        made sufficiently low so as to minimize the absorption of heat        released from the reaction in the drop in order to minimize        attenuation of the temperature change arising from the reaction.

Each thermal equilibrium region 120 and 125 contains thermometers 140and drop merging electrodes 130. Although for the purposes hereinthermometers 140 are shown spaced apart from more centrally-positioneddrop merging electrodes 130 on each thermal equilibrium region 120 and125, this configuration is for means of example only. Provided that thedrop merging device 130 and thermometers 140 are in good thermal contactwith the high conductance film, the exact placement of thermometers 140and drop merging electrodes 130 is not important for thermalconsiderations.

In operation, the two resistive thermometers 140 situated in thermalequilibrium region 120 detect the heat of reaction between an arbitraryprotein and a ligand at low concentrations deposited within thermalequilibrium region 120. In this example, the heat of reaction isdetected through measurement of a voltage change in a bridge circuit dueto the resistance change in the thermometers that are configured in thebridge circuit. This is an example of connecting or interconnectingcircuitry that allows “electrical detection” of an event orcharacteristic, such as detection of temperature or thermal signals orof a difference between two voltages, resistances, or temperatures,meaning that the circuitry provides or can be connected to circuitrythat provides an electrical signal indicating the detected event orcharacteristic. Within any circuitry, electrically conductive componentsthat serve primarily to connect other components are referred to hereinas “leads” or “lines.”

As used herein, the term “bridge” refers to any electrical instrument ornetwork for measuring or comparing resistances, inductances,capacitances, or impedances by comparing two voltages to each other orby comparing their ratio to a known ratio. Further, the terms “bridgecircuit” and “bridge circuitry” refer to circuits and circuitry thatconnect or interconnect resistive elements or other elements so thatthey can be used in a bridge. Bridge circuitry is “capable of beingdriven to allow electrical detection” of a characteristic, such asdetection of a difference between two voltages, resistances, ortemperatures, if the bridge circuitry is or can be connected to receivedrive signals and also is or can be connected to circuitry that providesan electrical signal indicating the detected characteristic when thebridge circuitry is receiving the drive signals.

Resistive thermometers 140 in thermal equilibrium region 120 detect areaction between a sample ligand and a protein; the other resistivethermometers 140 in thermal equilibrium region 125 serve as a reference.Because the temperature rise due to the reaction may be small, forexample approximately 10 μK for protein and ligand concentrations of 1μM and a heat of reaction of 10⁴ cal/mole, the resistive thermometers140 are fabricated from materials that provide a large change inresistance for a small temperature change.

In this implementation, the resistive thermometers 140 are fabricatedfrom high TCR material. Similar small drops of non-reactive solution(for example water or mixtures of water and DMSO) and target protein,the control combination, are deposited close together in thermalequilibrium region 125. Resistive thermometers 140 are configured as anAC bridge represented by AC generator 180 and ground 190, discussed inmore detail hereinbelow. At a specified time after the drops havereached thermal equilibrium, they are moved together to initiate thereaction. The movement operation creates sufficient mixing of the twodrops in a time small compared to the measurement time. The heatreleased by the protein-ligand reaction of the test combination causes achange in the resistance of the affected thermometers relative to thereference thermometers. This change in resistance causes the voltage atthe detection point to change from zero. This change is detected bysensitive, noise rejecting circuits such as a lock-in amplifier withindetection electronics 150.

FIGS. 2-4 show other implementations in which nanocalorimeter detectors200, 300, and 400 include thermal isolation layers 210, 310, and 410,respectively, which contain thermal equilibrium regions 220, 320, 420,and 425. Thermal isolation layers 210, 310, and 410 provide isolationfrom surrounding thermal environments, thus increasing measurement timeand reducing thermal noise.

In FIG. 2, thermal equilibrium region 220 contains one resistivethermometer 240, which measures the reaction temperature. In FIG. 3,thermal equilibrium region 320 contains two resistive thermometers 340,which measure the reaction temperature. In FIG. 4, thermal equilibriumregions 420 and 425 each contain two resistive thermometers 440, whichmeasure the reaction temperature. Each resistive thermometer is producedin thermal equilibrium region 220, 320, 420, or 425 usingmicrofabrication or other techniques, such as printed circuit boardfabrication techniques.

Thermal equilibrium regions 220, 320, 420, and 425 are each sufficientlylarge to receive and support separate drops of protein and liganddeposited by direct printing and also to support the combination ofthese two drops after merging, triggered by drop merging device 230,330, or 430. Thermal equilibrium regions 220, 320, 420, and 425 eachhave a sufficient thermal conduction for the region to equilibratequickly relative to the thermal dissipation. Each region also has asufficiently low heat capacity such that little of the heat of reactionis absorbed in the support. High thermal conductivity with low heatcapacity may be accomplished, for example, with a metal film such as a10 μm thick aluminum or copper film.

In addition to resistive thermometers, thermal equilibrium regions 220,320, 420, and 425 contain drop merging devices 230, 330, and 430,respectively. Although thermometers 240, 340, and 440 are shown spacedapart from more centrally-positioned drop merging devices 230, 330, and430 on thermal equilibrium regions 220, 320, 420, and 425, thisconfiguration is for example only. Provided that the drop merging device230, 330, or 430 and thermometer 240, 340, or 440 are in good thermalcontact with the high conductance film, the exact placement ofthermometer 240, 340, or 440 and drop merging device 230, 330, or 430 isnot important for thermal considerations.

In operation, resistive thermometers 240, 340, and 440 situated inthermal equilibrium regions 220, 320, 420, and 425 detect the heat ofreaction between reactants such as an arbitrary protein and a ligand atlow concentrations deposited within thermal equilibrium regions 220,320, 420, and 425, respectively. For example, resistive thermometers 440situated in thermal equilibrium region 420 detect the temperature ofdrops deposited and merged within thermal equilibrium region 420.Similar small drops of non-reactive solution (for example water ormixtures of water and DMSO) and target protein, the control combination,are deposited close together in thermal equilibrium region 425. In thisexample, the heat of reaction is detected through measurement of avoltage change in a bridge circuit due to the resistance change in thethermometers, which are configured in the bridge circuit.

In general, resistive thermometers 240, 340, and 440 in thermalequilibrium regions 220, 320, and 420 detect a reaction between a sampleligand and a protein or between other suitable reactants, whileresistive thermometers 440 in region 425 detect a reference reaction,such as between non-reacting fluids. Because the temperature rise due tothe reaction may be small (approximately 1 mK for the implementation ofFIG. 2 or, in other implementations, approximately 10 μK for protein andligand concentrations of 1 μM and a heat of reaction of 10⁴ cal/mole),resistive thermometers 240, 340, and 440 are fabricated from materialthat provides a large change in resistance for a small temperaturechange. In these implementations, resistive thermometers 240, 340, and440 are made of high TCR material.

Resistive thermometers 240 and 340 are each configured as one leg of anAC bridge, the other legs of which (i.e. any legs without resistivethermometers) are included in detection electronics 250. Other legs ofthe bridge are made, for example, of low temperature coefficientresistors located on an amplifier printed circuit board (PCB).Similarly, resistive thermometers 440 are configured as legs of anAC-biased Wheatstone bridge, driven between AC generator 480 and ground490, discussed in more detail hereinbelow.

At a specified time after the drops have reached thermal equilibrium,they are moved together to initiate the reaction. The movement operationcreates sufficient mixing of two drops in a time small compared to themeasurement time. The heat released by the protein-ligand reaction of atest combination causes a change in the resistance of affectedthermometers. This change in resistance causes voltage at a detectionpoint to change from zero. This change is detected by sensitive, noiserejecting circuitry such as a lock-in amplifier. Alternatively if thereactions to be measured produce enough heat, the resistance change ofone or more thermometers could be measured by a direct DC resistancemeasurement, such as through two thermometers connected in series.

FIG. 5 shows thermometers 510, 520, 530 and 540 forming four resistivelegs of one example configuration for a bridge circuit. Resistivethermometers simultaneously measure temperature changes due to both thereaction and the background drift. In this example, two measurementthermometers 530 and 540 measure the reaction and two referencethermometers 510 and 520 measure the background temperature changes. Ifthe resistance of the measurement thermometers changes, as happens whenthe temperature in the measurement region increases, then the voltage atoutput detection point R in the bridge becomes more positive or negativerelative to ground, depending on the polarity of the voltage placedacross the bridge circuit and the sign of the TCR, while the voltage atoutput detection point L in the bridge does the opposite, that is,becomes less positive or negative relative to ground, respectively. Thisconfiguration maximizes the voltage difference across detectionelectronics 550. As will be appreciated by one skilled in the art, otherbridge configurations are possible, such as one in which thermometer 540has a low temperature sensitivity and is not fabricated on the device orwhere thermometer 520 is replaced by a variable resistor used to balancethe bridge and is also not fabricated on the device.

Resistance thermometers 510, 520, 530 and 540 may be fabricated frompatterned thin film and are connected as a bridge. The resistance ofeach thermometer varies with temperature by an amount proportional tothe TCR of the material used. Sinceα=1/R(ΔR/ΔT),

-   -   it follows that        ΔR=αRΔT,    -   where R is resistance, T is temperature, and α is the TCR of the        thermometer material. Therefore, the signal voltage across the        resistor varies by        ${{\Delta\quad V_{S}} = {{\Delta\quad{RI}} = {\alpha\quad R\quad\Delta\quad T\sqrt{\frac{P}{R}}}}},$    -   where V_(S) is the signal voltage, I is the current through the        resistor, and P is power. The thermal noise in each resistor        becomes        V _(N)={square root}{square root over (4kTRB)}=1.2×10⁻¹⁰{square        root}{square root over (RB)}    -   where B is the measurement bandwidth in seconds, R is the        resistance in Ohms, and k is Boltzmann's constant. Assuming the        detection system can be constructed without introducing noise in        excess of the thermal noise, the signal to noise ratio becomes        S/N≅8.3×10⁹ αΔT{square root}{square root over (P/B)}.

Protein-ligand reactions are generally investigated at lowconcentrations during high-throughput screening, typically in the rangeof 10⁻⁵ to 10⁻⁶ M. The reactions typically release a heat of reaction,Q, which is on the order of 10⁴ cal/mole. For illustrative purposes,consider combining two drops with concentrations of 2 μM of protein andligand, respectively. If the drops have equal volumes, the combinationhas a 1 μM concentration of each reactant. Additionally,CVΔT=MVQ,

-   -   where V is the solution volume, C is the heat capacity of the        solution, and M is the concentration in the mixed drop.        Therefore,        ΔT=MQ/C=10⁻⁶ mole/L×10⁴ cal/mole/10³ cal/K-L=10⁻⁵ K,    -   where Q is the heat of reaction, C is the heat capacity of the        solute, and M is the concentration in the mixed drop.

For example, for a thin film thermometer made from a-Si, for whichα=2.8×10⁻² K⁻¹, and a bandwidth of 0.1 Hz, a signal to noise ratio of 7is achieved with 1 μW of power dissipated in the resistor. The voltagechange then becomesΔV _(S)=2ΔRI=2αΔTRI=4×10⁻⁷ RI≅4×10⁻⁷ {square root}{square root over(PR)}.

Table 2 of the parent application, incorporated herein by reference,provides the signal strength for various exemplary combinations ofthermometer impedance and power. In current implementations, thermometerimpedances are approximately 8 kΩ.

FIGS. 1-5 illustrate examples of devices, each of which includes asupport layer. Two or more resistive thermometer elements are on thesupport layer, together with bridge circuitry. The bridge circuitryelectrically connects first and second subsets of the thermometerelements in a bridge, and the bridge circuitry has one or more detectionpoints. The bridge circuitry is capable of being driven to allowelectrical detection, at the detection points, of differences betweenfirst and second temperature changes. The first temperature change isreceived by the first subset of the thermometer elements and the secondtemperature change is received by the second subset of the thermometerelements.

The techniques described above for implementing the devices shown inFIGS. 1-5 also illustrate a method of producing detecting devices. Themethod includes producing resistive thermometer elements and bridgecircuitry as described above. In particular, the thermometer elementsand the bridge circuitry are produced on a support layer.

To initiate a reaction, the deposited drops need to be merged togetherand the drop contents well mixed. It is noted that numerous methods fordrop deposition are known in the art, any of which may operatebeneficially for the purpose of dispersing drops.

Although numerous means and methods for merging the deposited drops maybe utilized, for the purposes herein, the exemplary methods disclosed inco-pending U.S. patent application Ser. No. 10/115,336 (U.S. PatentApplication Publication No. 2003/0183525), entitled “Apparatus andMethod for Using Electrostatic Force to Cause Fluid Movement”,incorporated herein by reference, will be briefly described. To reducecomplexity of the system and to increase reliability, this example dropmerging method utilizes electrostatic forces generated by a planarconfiguration of two electrodes to merge the two drops and causeequilibration through fast mixing. The electrodes can be thin conductingfilms produced on the surface of the device using microfabrication orother techniques, such as printed circuit board fabrication techniques.

FIG. 6 shows merging electrodes formed from conducting films 610 and620, which are positioned on the surface of substrate 650 and covered byinsulating layer 640. In this example, conducting films 610 and 620 maybe approximately 1.0 mm by 0.8 mm in size, with a thickness ranging insize from approximately 0.1 μm to approximately 10 μm, and are separatedby a gap of approximately 50 μm and are made of a thin film of aluminum,copper, chromium, titanium-tungsten (TiW), or a combination of them; theinsulating layer may be approximately 0.1 μm to approximately 2 μm inthickness and may, for example, be made of silicon oxide or siliconnitride or silicon oxynitride, or spin-, spray-, or otherwise depositedpolymers, such as parylene, Dupont Teflon® AF, 3M™ Fluorad™ products,3M™ EGC 1700, other fluoropolymers, polysiloxanes, diamond-like carbonor other spin-coated, spray-coated, dip coated, or vapor depositedpolymers. Suitable insulator materials have a high electricalresistivity, chemical and mechanical durability and have no pinholes indeposited thin film form. High conductance film 680 enables thermalequilibration in the thermal equilibrium region. Protein drop 660 isdeposited asymmetrically across the surface above conducting films 610and 620 such that the drop disproportionately occupies the surface aboveone of the conducting films. In this example, 70% of protein drop 660occupies the surface on the side of meridian 670 above conducting film620 and 30% of protein drop 660 occupies the surface on the side ofmeridian 670 above conducting film 610.

Ligand drop 630 is deposited on the surface above conducting film 610.When a voltage is applied, such as in the form of a voltage pulse,across conducting films 610 and 620, drop 660 is propelled towardstationary drop 630 and the drops merge. While the comparative dropsizes of protein drop 660 and ligand drop 630 may be equal, unequal dropsizes may also be used. The hydrophobic surface of insulating layer 640minimizes the adhesion of drops 630 and 660 to the surface, whichreduces the drag on the drops during merging. In this example, thehydrophobic surface is made of a fluorinated polymer, such as, forexample, 3M™ Fluorad™, Dupont Teflon® AF, 3M™ EGC-1700, orplasma-deposited fluorocarbons. In one implementation, a parylenecoating may be used as the insulator layer, as well as for thehydrophobic surface.

Alternatively, the thermometer material (e.g. amorphous silicon) itselfmay be utilized to construct drop mover electrodes. Also, the electrodesand thermometer may be fabricated in different layers, with theelectrodes in a layer between the drop deposition points and thethermometer, to enable placing metal drop mover electrodes on top of thethermometers. In this approach, an electrically insulating layerseparates the thermometers and electrodes.

The parent application, incorporated herein by reference, describesseveral available technologies for drop delivery, including syringes andother types of dispensers and techniques such as pin spotting.

FIG. 7 shows a schematic of a second implementation of an electronicmeasuring system. For the purposes of example, an alternating current(AC) detection method is illustrated. The AC detection method eliminatesthe 1/f noise inherent in electronic devices, in which the 1/f noise canbe significant at frequencies up to 1 kHz. A bridge circuit is used todetect changes in the resistance of the thermometers. The electroniccircuitry implements four functions: amplification of the output of thebridge, zeroing of the bridge, detection of the signal, and computeranalysis of the signal. To each bridge 710, a sine wave is provided bygenerator 780. This sine wave drives the two input terminals of eachbridge.

Each bridge has two output terminals whose difference represents thetemperature difference of the reference and measurement cells of thebridge. The signal on these two terminals is amplified by a low-noisesignal amplifier 720. Because the signal level is low, noise introducedby this function must be minimal, but noise minimization must bebalanced by design considerations. For example, for the array to bedisposable, which is desirable in some applications, the amplifiers mustbe located off the array, but amplifiers placed on the periphery resultin the introduction of noise through the longer lead length. To minimizenoise from interconnect, the amplifiers may be placed on a separatetemperature-controlled heat sink positioned in close proximity to thedetector array, with amplifiers 720 placed directly above the detectorarray and contacting the array through compressible pogo-pin connectors.An additional advantage of placing each amplifier directly above itsassociated bridge is that the bridge output signal wires do not have topass near any other wires, and thereby avoid noise coupling.

A multiplexer 730 enables several individual detectors to use onelock-in amplifier 760 and analog-to-digital (A-D) converter 770. Withthe implementation shown in FIG. 7, advantage is derived by the use ofone signal amplifier for each detector and placement of multiplexer 730after the amplifier. The noise introduced by the multiplexer contributesa smaller relative amount than if the multiplexer had been placed beforethe signal amplifier. Alternatively, if noise levels permit, themultiplexer could be placed before the signal amplifiers, allowing fewersignal amplifiers and a more compact arrangement of amplifiers andbridges.

The temperature sensors in each bridge may be similar but not identicalwith each other. After temperature equilibration, the output of thebridge will not quite be zero because of these differences. The outputwill be a small sine wave proportional to the difference. This commonmode signal, if not reduced, limits the amount of amplification betweenthe bridge and lock-in amplifier 760. This in turn limits the systemsensitivity. The common mode signal is minimized by a bridge zerooperation performed after the initial amplification through second stageamplifier 740, which also receives a signal from offset voltage source750. An offset control signal to source 750 selects a proportion of thesine wave reference signal to be subtracted out of the amplified inputsignal. This control signal is set by measuring output afterequilibration and then setting it to minimize the common mode output. Ifthe inherent balance of the bridge is sufficient, the offset amplifieris not needed.

Lock-in amplifier 760, which produces DC output indicating amplitude ofthe detector signal, may be implemented with known lock-in amplifiers orequivalent circuitry. Alternatively, the lock-in operation could beimplemented in software. In general, a lock-in amplifier can be used tomeasure signals buried in noise. A lock-in amplifier does this by actingas a narrow bandpass filter that removes much of the unwanted noisewhile allowing the signal being measured to pass through.

A standard lock-in amplifier known in the art includes a variable gaininput amplifier that increases input signal amplitude; a phase detector;and a low-pass filter with adjustable cut-off frequency. The lock-inamplifier receives an input signal with an unknown value and a referencesine wave at the frequency of modulation of the signal being measured.After input amplification, the input signal is mixed with the referencesignal (this operation is also known as phase detection) and then sentthrough the low-pass filter. This low-pass filtering effectively removessubstantially all electronic noise that is picked up between the source(in this case, the Wheatstone bridge) and the output. The DC-coupledoutput signal of the lock-in amplifier is proportional to the amplitudeof the input signal.

The analog output of the lock-in operation is digitized by A-D converter770 (conventionally included within lock-in amplifier 760, providing adigital output signal) and can be input into computer 790 for analysis.Amplitude of the digitized signal represents temperature difference onthe bridge. After the drops are moved together and when a reactionoccurs, the amplitude will increase until the drops are fully mixed andthen decrease as heat is removed through conduction and evaporation. Ifno reaction occurs, no significant change will occur in the amplitude.The computer can correlate the digitized signal against expectedtemperature increase and decrease. If the correlation is positive, thenthe occurrence of a reaction is signaled.

FIG. 8 shows detectors of a detector array arranged in a rectilinearorientation to form a matrix array. In this example, the array isfabricated on thin plastic sheet 810, for example a 12-24 μm thickKapton® plastic substrate, and is supported by heat sink 820, which ismade of a material with a high thermal conductivity such as Cu or Al.Thin film conducting lines 850 placed in the regions between individualdetectors 830 serve as electrical interconnect that carry signal andpower between the detectors and the electronic module on the outside.Detectors 830 require interconnect for signal excitation and dropmerging electrodes. All detectors in pairs of adjacent rows areconnected to common merge-electrode power 880.

The resistive thermometers, drop merging electrodes, and electricalinterconnect may be patterned on one side of the matrix array, and thethermal equilibration film may be fabricated on the other side.Measurements can be made simultaneously in two rows. Detector signal andground are provided through contact pads located over the heat sinkadjacent to each detector and connected to the array through detectoramp contact pads 840. Common bridge-excitation is provided for pairs ofrows by bridge power conducting lines 870. The merge-electrode power andcommon bridge-excitation are introduced through alternating rows.Because it is desirable to transfer fluids from standard storagedevices, such as well-plates having different densities (96 well, 384well, or 1536 well) the detectors have the same 9 mm square layout asstandard 96 well-plates used in the biotechnology and pharmaceuticalindustries.

An array like that in FIG. 8 illustrates an example of an array with asupport layer and not less than one detector on the support layer. Eachdetector includes two or more resistive thermometer elements on thesupport layer, together with bridge circuitry. The bridge circuitryelectrically connects first and second subsets of the thermometerelements in a bridge, and the bridge circuitry has one or more detectionpoints. The bridge circuitry is capable of being driven to allowelectrical detection, at the detection points, of differences betweenfirst and second temperature changes. The first temperature change isreceived by the first subset of the thermometer elements and the secondtemperature change is received by the second subset of the thermometerelements.

The above-described techniques for producing the array of FIG. 8 alsoillustrate an example of a method of producing detectors that includesproducing resistive thermometer elements and bridge circuitry asdescribed above. More particularly, the thermometer elements and thebridge circuitry are produced on a support layer.

FIG. 9 shows a cross-section of the nanocalorimeter assembly and itsdetector environment, which provides thermal isolation, electricalconnections and sample delivery. To achieve thermal isolation, theenvironment is structured to insure that the heat transferred to or fromthe drop is minimized to a value as close to zero as possible; onetechnique employs a cap over a sensing region, as described in relationto FIG. 19 of copending U.S. patent application Ser. No. 11/______[Attorney Docket No. A1578-US-CIP4/U1047/012], entitled “ThermalSensing” and incorporated herein by reference; another approach is toperform signal processing on resulting data to correct for heattransfer. The three main heat transfer channels for the assemblyinclude: thermal conduction through the air, thermal conduction acrossthe supporting medium, and evaporation, with evaporation being muchlarger than the others.

To reduce evaporation to acceptable limits, measurements can beconducted at low temperatures and high humidities, for example 5° C. innear 100% relative humidity (e.g. noncondensing). Specifically,evaporation is controlled in part by maintaining near 100% relativehumidity, within some acceptable tolerance, of the solvent used todissolve the chemicals being investigated. This may be accomplished byexposing a reservoir of solvent to the atmosphere in the chamberenclosing the detector. The lower temperature reduces the vapor pressureof the solvent, and higher humidities reduce the concentration gradientof solvent in the gas phase near the surface of the drop, therebyreducing the driving force for evaporation. In other implementations,reasonable measurements might be attainable at higher temperatures orlower humidities despite the correspondingly higher evaporation rates,in which cases operation at low temperatures or high humidities may notbe necessary.

Thermal conductivity through the surrounding environment can be reducedthrough use of a controlled atmosphere, for example an environment richin xenon or argon, which have lower thermal conductivities than air.Conductivity can also be controlled through the use of a partial orcomplete vacuum, aerogels or other insulating materials, and othermethods that will occur to those skilled in the art.

To minimize thermal conduction across the supporting medium, detector910 resides on substrate 915, which is supported by substrate carrier925, which is in contact with heat sink 920. In this example heat sink920 is comprised of copper, but other materials known in the art couldalso be utilized. Heat sink 920 may be in thermal contact with anoptional active temperature control device 930, which controls thetemperature of the heat sink to within 1 mK to 0.1 K of amplifier heatsink 940.

The detector amplifiers dissipate power (10 mW each), which may be toomuch heat for the detector heat sink in some implementations. Theamplifier power can be sunk to a separate heat sink if desired. Signalamplifiers 990 reside on amplifier printed circuit board (PCB) 950,which is in contact with heat sink 940. The temperature of heat sink 940can be controlled by a temperature control device 960, if desired for aparticular implementation. Pogo-pin connectors 980 connect amplifier PCB950 with detector substrate 915 through amplifier pads 970.

There are several conditions in which the heat sink 920 does not need tobe temperature controlled. In these cases, the heat sink is thermallyisolated from the enclosing chamber using standard low conductionmaterials like glass, plastic or stainless steel tubing. In these cases,the amplifier PCB 950 is placed in direct contact with the temperaturecontrolled enclosing chamber.

Tables 3 and 4 and the related description in the parent application,incorporated herein by reference, illustrate the magnitude oftemperature fluctuations that heat sink 920 may experience.

FIG. 10 illustrates a cross section of a measurement system utilizingthe array described above. The measurement system in this exampleconfiguration includes two compartments, load lock chamber 1010 andmeasurement chamber 1050. The chambers and the atmosphere containedwithin them are equivalent; they are at the same operating temperature.The atmosphere within each chamber is a non-reactive gas, for examplexenon, argon, air, or nitrogen, at a near 100% relative humidity for thesolvents used in the drops being measured, and this humidity level ismaintained through use of vapor pressure reservoirs 1045. Thetemperature of the chamber walls is controlled to within 0.1 K. Heatsink 1085, mounted on heat conductor 1090, receives heat from the powerdissipated in the measurement thermometers on detector array 1040 whenin the measurement chamber 1050. In this example four thermometers areused for each detector, as shown in FIG. 1, and each thermometerdissipates approximately 4 μW. The rate of temperature increase of heatsink 1085 due to thermometer heating is approximately 10 μK during a 10second measurement, based on a 96 detector array and a heat sink with aheat capacity of 1500 J/K (refer to Table 3 above). Detector array 1040is connected to detector array electronics 1030 which in turn areconnected to system electronics 1060. Biomaterials are contained withina biomaterial storage well plate 1015, which is placed in the load lockchamber 1010. In the measurement chamber 1050 are detector electronics1075 as well as the associated heat sink/controller 1070 for thedetector electronics.

Biomaterials 1025 are deposited on the array with chemical depositiondevice 1035 in preparation for the measurement. While in the load lockchamber 1010, the heat sink 1085 and associated detector 1040 andbiomaterials 1025 are brought into thermal equilibrium with the chamberthrough heat conductor 1095. Heat conductor 1095 may be any material orsystem of high thermal conductivity, and may be, for example, a metalblock such as copper or aluminum that is in good thermal contact withboth the chamber wall and the heat sink 1085. As shown in FIG. 10,thermal contact of heat conductor 1095 with heat sink 1085 occursthrough the array transporter 1020. However, this configuration isexemplary only; other configurations will occur to those skilled in theart and are contemplated by the disclosure herein.

In alternative implementations, heat conductor 1095 may have activetemperature control, such as control by a circulating-fluidrefrigeration or heating system, a Peltier device, a resistive heater, aheat pump, or any of a number of other active temperature-controldevices known by those skilled in the art. Furthermore, the heatconductor and associated temperature control function can be integratedinto the array transporter 1020. Array transporter 1020 moves a detectorarray with deposited biomaterials from the load lock into measurementchamber 1050 and, in this example, utilizes a circular motion so that adetector array with measured materials is simultaneously moved from themeasurement chamber to the load lock. Other array transport methods maybe utilized, such as pick-and-place devices and belt devices withelevators.

Once in the measurement chamber, the detector array is raised intocontact with the pogo pins, and simultaneously the heat sink 1085 (withheat conductor 1090) is raised above the transporter 1020 and thermallyisolated from it by supporting pins 1053. The supporting pins may befabricated from any good thermal insulating material with sufficientmechanical strength, such as glass rods, stainless steel hollow tubing,plastic rods, porous ceramics, and other materials known to thoseskilled in the art. Other configurations are possible; for example, atemperature controller may be used to maintain heat sink 1085 at aspecified temperature in measurement chamber 1050, for example within 1mK of the temperature of heat sink/controller 1070 of detectorelectronics 1075, rather than relying on thermal isolation alone.Pogo-pin detector connectors 1080 make electrical contact directly tothe detectors to transmit thermal change information from the detectorarray to detector electronics 1075. This type of connector is used inthis example to provide a nonpermanent connection that allows connectionto be made to successive arrays with low thermal contact to the arrayand good placement accuracy with a small foot-print that providessymmetrical contact to the measurement and reference regions to enableprecise differential measurements.

In operation, detector array 1040 is placed in load lock chamber 1010while a previously set-up detector array 1055 is being measured inmeasurement chamber 1050. The initial temperature of detector array 1040could, for example, be within 1 K of the temperature of load lockchamber 1010, or measurement could be timed to avoid this and othertemperature constraints. The proximity of measurement chamber 1050 toload lock chamber 1010 enables the connected detector array to be movedbetween the chambers while remaining in a controlled environment.Biomaterials are then moved into load lock chamber 1010 and stored in anappropriate vehicle 1015, such as a 384 or 1536 well plate, althoughother containers or well plate sizes would also be appropriate.Biomaterials 1025 are then deposited on detector array 1040 using, forexample, an aspirating/printing system or an automated syringe-typeloader 1035. Deposition device 1035 is maintained at a controlledtemperature to avoid warming biomaterials 1025. Initially, detectorarray 1040 is connected to detector array electronics 1030 and systemelectronics connector 1060, which provides the necessary electricalconnections to all the detector elements in detector array 1040 with theexception of the detector electronics for the measurement bridge.Depending on conditions, the detector bridges in detector array 1040 maybe driven by the AC sine wave (for example, element 560 in FIG. 5) toself-heat to a temperature that equilibrates the drop temperature withthe controlled environment in the load lock chamber. This signal isconducted through the system electronics connector 1060 to the detectorarray electronics 1030.

After the deposited materials 1025 come to thermal equilibrium with thedetector array 1040, the detector array 1040 with deposited chemicals1025 is then moved from load lock chamber 1010 to measurement chamber1050 by array transporter 1020 and measured detector array 1055 is movedinto load lock chamber 1010. This movement may be accomplished through arotation, such as a 180-degree rotation, or by any other means known inthe art. Within measurement chamber 1050, the detector array is inthermal contact with heat sink 1085, which in this implementation isthermally isolated from transporter 1020 by supporting pins 1053 inmeasurement chamber 1050. The measurement sequence is initiated byapplying the AC sine wave to the detector bridges. This signal iscreated by an AC generator located on the amplifier PCB 1075 andconducted to detector array 1055 through the pogo pins 1080. Thedetector bridge is then zeroed by properly setting the offset voltage.Thermal equilibration is confirmed by measuring the voltage across thedetector bridge for a short period of time. When the rate of change ofthis voltage is below a pre-specified level, the system is in thermalequilibrium. The zeroing operation may need to be repeated during thisprocess.

A row of drops of deposited chemicals 1025 is then merged and mixed onthe surface of the detector array. This is accomplished by applying adrop moving voltage from the amplifier PCB 1075 through the pogo pins1080 to the detector array 1055. The transient voltages generated fromthe merging voltages are allowed to dissipate. The reaction duringmixing is then measured by detecting the imbalance in the bridge. Eachbridge in the row is measured repeatedly for a period of time and thedata is input into the computer for analysis.

Merging drops in this way illustrates an example of a method of using adevice as described above. The method includes depositing drops of fluidon a reaction surface and a reference surface. The method also includessimultaneously activating drop merging electrodes in the regions thatinclude the reaction surface and the reference surface to causesimultaneous reactions on the surfaces.

Simultaneous activation of drop merging electrodes is advantageousbecause it allows minimization of background changes due to changes indrop surface area caused by different evaporation rates or other causes.Background changes can be minimized because the reactions in themeasuring region and the reference region are activated simultaneously.In the meantime, appropriate signals can be provided to the bridgecircuitry to allow detection of a voltage difference between thedetection points. In other words, detection can be an ongoing processthat begins before the merging electrodes are activated, with thefeedthrough from the drop merge signal available as an indicator thatthe reaction has begun.

The individual bridges in a single row may be multiplexed in thedetection electronics. A measurement is made on one detector and thenthe next detector in the row until all the detectors in the row havebeen measured. This is repeated for a period of time until allmeasurements for the row are complete. Alternatively, multiple instancesof the detection electronics can simultaneously measure all the detectorarrays in the row. To further reduce measurement time, measurements maybe performed in blocks of two or more rows.

FIG. 11 is a schematic diagram of an electronic measuring system similarto that shown in FIG. 5, but with different details. Measuring system1100 includes thermistor bridge 1102, instrumentation amplifier 1104,and lock-in amplifier 1106.

The term “thermal input signal” refers herein to a signal provided to acomponent in the form of thermal change, and the thermistors inthermistor bridge 1102 receive different thermal input signals.Thermistor bridge 1102 includes two pairs of opposite thermistors,arranged in a Wheatstone bridge that suppresses, to the first order,common-mode variations, i.e. variations in output signal as a result ofcommon variations in resistance of all the thermistors. Implementationsof low noise thermistors and related techniques are described in greaterdetail in co-pending U.S. patent application Ser. No. 11/______[Attorney Docket No. A1578-US-CIP2/U1047/008], entitled “ResistiveThermal Sensing” and incorporated herein by reference in its entirety.

Thermistors 1110, referred to as “measuring thermistors,” are located sothat they are exposed to a thermal input signal that is being measured,while thermistors 1112, referred to as “reference thermistors,” arelocated to make a reference measurement. For example, if the thermaleffect of a reaction is being measured, thermistors 1110 can be locatedso that a thermal signal indicating heat from the reaction would beconducted or otherwise provided to them, while thermistors 1112 can belocated away from and insulated from the reaction so that they receiveno such thermal signal.

Instrumentation amplifier 1104 amplifies the difference voltage betweennodes 1114 and 1116 of bridge 1102 and can be implemented as alow-noise, very high impedance amplifier. Its output is provided tolock-in amplifier 1106, which performs second stage amplification,removing additive voltage noise by bandwidth narrowing. The voltage VBprovided to bridge 1102 is a sinusoidal voltage derived from theinternal reference voltage source 1120 of lock-in amplifier 1106.Lock-in amplifier 1106 also includes an amplifying component 1122 thatreceives the reference voltage and the output from instrumentationamplifier 1104 and provides the output signal V_(out). V_(out) isproportional to the difference between the temperature sensed by themeasuring thermistors 1110 and the temperature sensed by the referencethermistors 1112.

The circuitry in FIG. 11 can generally be implemented with standardelectrical components, except that bridge 1102 includes thermistors withparticular noise properties under a device's operating conditions. Forexample, they can be low noise thermistors or they can be thermistorsthat include materials with specific noise characteristics. In a lownoise implementation, instrumentation amplifier 1104 and other resistors(not shown) would also be selected for low noise characteristics underthe device's operating conditions. The term “operating conditions” isused herein to refer to the relevant conditions under which acalorimeter or other thermal sensing device is designed to operate, suchas dissipated power, bias voltage, ambient temperature, and so forth.

As used herein, a “low noise thermal sensor” is a thermal sensor forwhich the noise equivalent temperature difference (NETD) is not greaterthan approximately 50 μK over a typical thermal sensing bandwidth rangeof approximately 3 Hz or more under a device's operating conditions; atypical thermal sensing bandwidth range is 0.1 Hz to 4.2 Hz, forexample, and a bandwidth range of 1 Hz to 4.2 Hz is also useful in somesituations. NETD of a thermal sensor refers herein to the apparenttemperature difference between an object and its surroundings thatproduces an effect equal to the intrinsic noise of the sensor; it couldalso be described as the differential temperature at which the signal tonoise ratio of the sensor is unity. A “low noise thermistor” isaccordingly a thermistor that can be used in a low noise thermal sensor.

Also, a thermistor that does not fall precisely within the abovedefinition of a low noise thermistor could be advantageously used inbridge 1102. For example, if bridge 1102 includes thermistors withvanadium oxide (VO_(x)) deposited at room temperature, bridge 1102 caneasily have NETD not greater than approximately 100 μK over a thermalsensing bandwidth range of approximately 3 Hz or more under acalorimeter's operating conditions; as described in greater detailbelow, VO_(x) thermistors have been fabricated and included in thermalsensors with NETD not greater than approximately 35 μK or even 10 μKover a bandwidth range of 1 Hz to 4.2 Hz under appropriate operatingconditions. This is advantageous because deposition of VO_(x) at roomtemperature is consistent with fabrication on substrates such aspolyimide, which is not readily compatible with the temperaturesnecessary for PECVD deposition of amorphous silicon, a frequently usedthermistor material.

In general, resolution of a temperature measurement made by system 1100in FIG. 11 is limited by several factors: Thermistor noise; contactnoise, such as from pogo pin contacts or other contacts; otherelectrical noise, such as from the amplifiers; TCR of each thermistor;maximum bridge supply voltage V_(B) allowed; and limits in thecommon-mode rejection ratio of the Wheatstone bridge. By performing anoise analysis on an implementation of system 1100, it is possible tooptimize electrical components for noise. For example, lock-in amplifier1106, with a reference frequency typically around 1000 Hz, suppressesmost of the 1/f (low frequency) noise originating from the electronicsitself or the environment.

The amplifier portion of system 1100 can also be empirically calibratedby connecting it to dummy metal film resistor bridges, in which case themeasured noise lies close to the theoretical Johnson noise, also knownas thermal noise, i.e. the theoretical minimum achievable noise level;specifically, the measured noise in such a setup is typically a factorof 2 greater than the theoretical Johnson noise. Actual measurements ofcontact noise from pogo pin contacts indicate that this noise does notplay a significant role at current noise levels, though it might if evenlower noise levels can be achieved. Maximum bridge supply voltage V_(B)is limited by self-heating and by the input range of instrumentationamplifier 1104. More specifically, offset arises because the thermistorsin bridge 1102 are not ideally matched, and the offset causes limitedcommon-mode rejection through differential self-heating, as well ascausing amplifier input range limitations. Small thermal imbalances andfluctuations between measuring thermistors 1110 and referencethermistors 1112 also limit common-mode rejection and measurementresolution because they result in erroneous signals.

After optimizing other components for noise, it is still possible toobtain further improvement by optimizing thermistors 1110 and 1112, bothfor noise and for TCR. Both noise and TCR of the thermistor materialaffect the NETD of the thermal sensor, which is used as a figure ofmerit for the sensor. Assuming that a thermistor's resistance is alinear function of temperature, which is a valid approximation for smalltemperature variations, and that the four resistors in the Wheatstonebridge are well-matched, the NETD of bridge 1102 can be calculated asfollows: $\begin{matrix}{{NETD} = \frac{2 \cdot V_{noise}}{V_{bridge} \cdot {TCR}}} & \left( {{Eq}.\quad 1} \right)\end{matrix}$where V_(bridge)=V_(B) in the implementation of FIG. 11 and V_(noise) isan observed noise voltage at nodes 1114 and 1116.

FIG. 12 shows a top plan view of a pair of thermistors 1140 that can beused in bridge 1102 in FIG. 11, either thermistors 1110 or thermistors1112. Each thermistor includes a rectangular slab of thermistormaterial, with slab 1142 being on the left in FIG. 12 and slab 1144 onthe right. Each slab has dimensions W and L, which are illustrativelyshown for slab 1142, and the dimensions of slab 1144 are substantiallyidentical. Leads 1150 and 1152 have interdigitated lines that extendacross slab 1142, while leads 1154 and 1156 have interdigitated linesthat extend across slab 1144. On the opposite side of layer 1162 fromslabs 1142 and 1144 is thermally conductive component 1160, whichextends to an adjacent region at which it is exposed to the temperatureeither of a reaction or a reference. When the reaction occurs within afluid drop under control of drop merging electrodes, component 1160thermally couples the drop with slabs 1142 and 1144, providing athermally conductive path from the drop to thermal sensors that includeslabs 1142 and 1144.

FIG. 13 shows thermistor pair 1140 in cross-section along the line 13-13in FIG. 12. Polymer layer 1162 can, for example, be a 1 mil (25.4 μm)thick polyimide layer, such as Kapton® film from DuPont, on which othercomponents are microfabricated in a manner described in greater detailbelow in relation to FIG. 15. Polymer layer 1162 provides thermalisolation between thermistor pair 1140 and other components, and, forthis purpose, any other suitable thermally isolating film could be usedinstead of polymer, including inorganic materials.

Thermally conductive component 1160 is on the lower surface of polymerlayer 1162, and can include thermally conductive metal such as copper oraluminum at a thickness of 9 μm or thinner; in general, component 1160can include any thermally conductive material and desired conduction canbe obtained by adjusting thickness in proportion to the material'sthermal conductivity.

Deposited over thermally conductive component 1160 is anti-couplinglayer 1164, which could be implemented as a 10 nm thick layer of gold,and functions to prevent capacitive coupling between adjacent parts ofthermally conductive component 1160; because it is very thin, layer 1164has low thermal conductivity, preserving thermal isolation. Layer 1164is believed to reduce noise by coupling component 1160 to ground,preventing slabs 1142 and 1144 from capacitively accumulating additionalcharge that could affect their response to thermal input signals.Implementations of layer 1164 and of other applicable anti-couplingmeasures are described in greater detail in co-pending U.S. patentapplication Ser. No. 11/______ [Attorney Docket No.A1578-US-CIP4/U1047/012], entitled “Thermal Sensing” and incorporatedherein by reference in its entirety.

On the upper side of polymer layer 1162, barrier layer 1170 protectsagainst contaminants and humidity, increasing device performance;barrier layer 1170 has been successfully implemented with a layer ofapproximately 300 nm of silicon oxynitride (SiO_(x)N_(y)). Slabs 1142and 1144 are on barrier layer 1170, and include material making itpossible for thermistor pair 1140 to be low noise thermistors. Leads1150, 1152, 1154 and 1156 are on slabs 1142 and 1144 and, in places, onbarrier layer 1170; leads 1150 can be implemented, for example, with asuitable conductive metal sandwich such as Cr/Al/Cr or TiW/Al/Cr toprovide electrical contact with slabs 1142 and 1144 and to provideconductive paths to other circuitry discussed in greater detail below.

Additional layers deposited over leads 1150, 1152, 1154, and 1156provide electrical passivation, environmental barriers, and hydrophobicsurfaces, which are especially useful for a system in which temperatureof reactions between fluids are measured through drop deposition andmerging. In FIG. 13, these layers illustratively include protectivelayer 1172 and polymer layer 1174. Protective layer 1172 can be producedby plasma-enhanced chemical vapor deposition (PECVD) of siliconoxynitride, while polymer layer 1174 can include a layer of parylene toprovide a barrier to liquid and to electrical leakage and to providesome hydrophobicity. Fluorocarbon polymer can be dip coated over theparylene to obtain a more hydrophobic surface. Alternatively, polymerlayer 1174 could include a Teflon® coating from DuPont or a similarmaterial.

FIG. 14 illustrates a thermal sensing cell 1200 that includes two pairsof thermal sensors like those shown in FIGS. 12 and 13. Frame 1202(shown in dashed lines) supports polymer layer 1162 (FIG. 13) fromunderneath. In addition, islands 1204 and 1206 (shown in dashed lines)are on the underside of polymer layer 1162 and each can be implementedlike thermally conductive component 1160 (FIG. 12). As described in moredetail below, these and other components of cell 1200 are generallysymmetrical about axis of symmetry 1208, with the left and right sidesof the cell being nearly mirror images of each other. Axis 1208 isapproximately straight and extends across polymer layer 1162.

Frame 1202 illustratively has alignment structures 1210 at the cornersof a recess within which islands 1204 and 1206 are positioned. Frame1202 can, for example, be formed from 1 mm thick stainless steel inwhich alignment structures 1210 and the recess for islands 1204 and 1206are etched, and the recess can then provide thermal isolation betweenislands 1204 and 1206 as well as between either of the islands and frame1202. Thermal isolation could be maintained in various other ways.

Contact pads 1212, 1214, 1216, 1218, 1220, 1222, and 1224 are on theupper surface of polymer layer 1162 over frame 1202. Each contact pad(except contact pad 1214) is connected to one or more of the componentsover islands 1204 and 1206 by leads that are shown schematically in FIG.14. If cell 1200 is approximately square with 9 mm sides, the contactpads can be approximately 1 mm×1 mm, allowing connection with pogo pins.The leads can be approximately 50 μm wide or even wider as long as theydo not result in loss of thermal isolation.

Thermistor slabs 1230, 1232, 1234, and 1236 can each be implemented asdescribed above for thermistor slabs 1142 and 1144 (FIGS. 12 and 13),providing two thermistor pairs, one with slabs 1230 and 1232 and theother with slabs 1234 and 1236. The contact pads could be connected invarious ways to provide an implementation of bridge 1102. For example,voltage VB can be applied to one of contact pads 1212 and 1216 while theother is connected to ground to provide a Wheatstone bridge with contactpad 1218 connected to one of nodes 1114 and 1116 and with contact pad1220 connected to the other. Therefore, one of the thermistor pairsincludes measuring thermistors 1110 while the other includes referencethermistors 1112, as can be understood by comparing with bridge 1102 inFIG. 11.

The contact pads in FIG. 14 can be electrically contacted with anysuitable connectors such as pogo pins, both for controlling drop mergerelectrodes and for electrically detecting thermal signals in the bridge.With a polymer layer substrate, crossing lines and vias are problematic.The layout in FIG. 14 provides a simpler layout with no crossing linesand with no vias, in part because all circuitry is within the cell'sregion, and none of the circuitry extends or connects electricallyoutside the cell's region except through contact pads. This techniquealso avoids long, unreliable lines that, if broken, could disable anentire row or column of an array.

FIG. 14 also shows drop mergers 1240 and 1242, on one of which areaction can be caused and differential temperature measurementperformed. Drop mergers 1240 and 1242 illustratively have chevron shapedfeatures, but could also be implemented by any of the techniquesdescribed in co-pending U.S. patent application Ser. No. 11/018,757entitled “Apparatus and Method for Improved Electrostatic Drop Mergingand Mixing”, incorporated by reference herein in its entirety.Conductive line 1244 extends from pad 1224 to the upper part of dropmerger 1242, conductive line 1246 extends between the upper parts ofdrop mergers 1240 and 1242, and conductive line 1248 extends leftwardfrom the upper part of drop merger to provide some symmetry withconductive line 1244. Pad 1222 is connected to the lower parts of bothdrop mergers by another conductive line. The conductive lines connectedto drop mergers 1240 and 1242 thus illustrate an example of reactioncontrol lines connected to drop merging electrodes in two regions,connected so that the drop merging electrodes are simultaneouslyactivated. Description of features shown in FIG. 14 that relate toproviding signals through contact pads and electrical detection throughcontact pads are described in co-pending U.S. patent application Ser.No. 11/______ [Attorney Docket No. A1578-US-CIP5/U1047/013], entitled“Thermal Sensing” and incorporated herein by reference in its entirety.

If a Wheatstone bridge like bridge 1102 is fabricated with elements thatare not identical, the bridge has a non-zero “offset voltage” or is“unbalanced”, meaning voltage measured across the bridge whentemperatures of all thermal sensors are equal; offset voltage can havezero frequency (DC) and non-zero frequency (AC) components. If thebridge's offset voltage is sufficiently great, additional circuitry maybe necessary to perform offset voltage correction. The need foradditional circuitry depends, of course, on the application, includingthe range of amplitude of the signals being detected and the sensitivityof circuitry that detects voltage across the bridge. In other words, anapplication of a bridge as described above has a “sensitivity limit”,meaning the amplitude of the bridge's offset voltage that wouldinterfere with accurate detection of the signal being detected; anoffset voltage above the sensitivity limit would cause loss ofinformation from the input signal, information whose detection isnecessary for the application to satisfy the relevant performancecriteria.

Although it is not possible in practice to produce a bridge with fouridentical elements, the components of the four elements can be shapedand positioned so that offset voltage is below the sensitivity limit forthe application despite process variations in patterning layers ofmaterial. As used herein, the term “process variations” includes notonly variations such as lateral or rotational movements of masks butalso different rates of etching in different directions and othervariations during fabrication that can result in difference between afinished pattern and its design.

As will be understood more fully from the description of FIG. 15 below,thermistor slabs 1230, 1232, 1234, and 1236 are patterned from a layerof semiconductor material. Part of the bridge circuitry, on the otherhand, is patterned from a layer of conductive material such as metal orheavily doped semiconductor material; components patterned from thislayer include interdigitated conductive lines that extend across andelectrically contact upper surfaces of the slabs and conductive leadsthat connect the interdigitated lines to each other and to contact pads1212, 1216, 1218, and 1220.

FIG. 14 illustrates several examples of how components can be shaped andpositioned to keep offset voltage below a sensitivity limit despiteprocess variations: Slabs 1230, 1232, 1234, and 1236, for example, have“overlay symmetry”, meaning that one could pick up one pair and put iton the other without changing orientation and the two would be virtuallyidentical; as a result, a shift of a mask during patterning of thesemiconductor layer would not cause a difference in slab shape.Similarly, interdigitated conductive lines are all parallel to axis1208, so that they are also tolerant of lateral mask shifts. Also, linesand semiconductor slabs overlap sufficiently that expected misalignmentwould not result in a short, an open, or another electrical change suchas changed resistance; examples of overlap can be seen in both of FIGS.12 and 14, where each interdigitated line extends beyond and overlapsthe upper and lower sides of the slab it contacts and each slab extendsbeyond and overlaps the outer boundaries of the leftmost and rightmostinterdigitated lines that contact it.

Furthermore, left-right symmetry about axis 1208 is another example ofshaping and positioning components so that bridge offset voltage isbelow a sensitivity limit. In addition to the left-right symmetry ofthermal sensors, thermally conductive components, drop mergers, andcontact pads, the implementation of FIG. 14 illustrates a substantialdegree of left-right symmetry in conductive lines and leads, madepossible by the left-right symmetry of other components.

As shown, the rectangular slabs are left-right symmetrical with theirlengthwise dimensions all aligned and with their widths all containedwithin a transverse strip extending substantially perpendicular to andacross axis 1208. This allows left-right symmetry of the interdigitatedlines extending across the slabs. Nevertheless, it has not provedfeasible to symmetrically lay out all the transverse leads, i.e. leadsthat extend substantially parallel to the transverse strip and connectto the interdigitated lines. In the implementation of FIG. 14, none ofthe transverse leads can be characterized as completely left-rightsymmetric.

Although not readily apparent in FIG. 14, it is also important thatvariations in thickness of the slabs be minimized. For example, toachieve thermistor resistances that differ by no more than 0.1%, thethicknesses of the slabs need to differ by no more than 0.1%. For a slabthickness of 300 nm, the difference must therefore not exceed 0.3 nm, anaccuracy on the order of a few atom layers of material. Therefore, thethickness of the layer of material from which the slabs are formed mustbe produced with very high accuracy.

The features described above tend to minimize DC offset voltageresulting from shape and position differences of components withindifferent bridge elements. Sometimes however, AC offset voltage canarise due to capacitive effects.

Also, connecting conductive leads are positioned relative to slabs suchthat a movement of the mask for one or both of the layers hasapproximately the same effect on relative position of slabs andconductive leads. As a result, capacitive interactions between slabs andconductive leads remain approximately equal among the bridge elements.This and similar features tend to minimize AC offset voltage resultingfrom different spacings and other positioning differences betweencomponents within bridge elements.

The implementation in FIGS. 12-14 illustrates an example of a device inwhich first and second subsets of thermometer elements are on left andright sides, respectively, of a symmetry axis extending across a supportlayer between two regions. The first and second subsets aresubstantially symmetrical with respect to each other about the symmetryaxis. In addition, the device includes first and second thermallyconductive structures having thermal contact with the first and secondsubsets of thermometer elements, respectively, and the thermallyconductive structures are also on the left and right sides of thesymmetry axis and are substantially symmetrical with respect to eachother about the symmetry axis.

The implementation of FIGS. 12-14 also illustrates an example of leftand right sets of resistive thermal sensors that are substantiallysymmetrical about a symmetry axis and that are within a layeredstructure at one surface of a support structure. On the same surface areleft and right input elements that receive thermal input and are alsosubstantially symmetrical about the symmetry axis. The same structurealso includes connection elements that electrically connect the thermalsensors in a bridge. On the opposite surface of the support structure isanother layered structure that includes left and right components, eachwith a thermally conductive path extending between opposite therespective input element and opposite the respective set of thermalsensors. The left and right components are also substantiallysymmetrical with respect to each other about the symmetry axis.

FIG. 15 shows several cross-sections in producing thermal sensing cell1200, taken along line 15-15 in FIGS. 12 and 14. As can be seen fromFIG. 12, line 15-15 extends through the middle digit of lead 1152 whereit extends over slab 1142. The operations illustrated in FIG. 15 aresimilar to those described in Torres, F. E., Kuhn, P., De Bruyker, D.,Bell, A. G., Wolkin, M. V., Peeters, E., Williamson, J. R., Anderson, G.B., Schmitz, G. P., Recht, M. I., Schweizer, S., Scott, L. G., Ho, J.H., Elrod, S. A., Schultz, P. G., Lerner, R. A., and Bruce, R. H.,“Enthalpy arrays”, Proceedings of the National Academy of Sciences, Vol.101, No. 26, Jun. 29, 2004, pp. 9517-9522 (“the Torres et al. article”),incorporated herein by reference in its entirety.

Prior to cross-section 1250 in FIG. 15, polymer layer 1162 is preparedfor subsequent operations. As noted above, polymer layer 1162 can be a 1mil (25.4 μm) or ½ mil (12.7 μm) thick Kapton® film or other polyimidefilm and is generally held flat during processing, because flatness isimportant for photolithography and for uniform feature sizes. Prior todeposition of material on polymer layer 1162, the surfaces of layer 1162are cleaned, and layer 1162 is stretched and mounted by lamination on aframe (not shown). Mounting layer 1162 on a stainless steel frameprevents it from curling or cracking during processing.

Cross-section 1250 shows a portion of polymer layer 1162 on whichbarrier layer 1170 has been deposited. Barrier layer 1170 has beensuccessfully implemented with a PECVD silicon oxynitride deposited to athickness of 300 nm, which has been successful in producing a low noisethermistor; other materials may also be suitable, including insulatingfilms such as sputtered SiO₂ or PECVD SiO or SiN. When properlydeposited, barrier layer 1170 provides improved surface smoothness and ahumidity and contamination barrier.

Cross-section 1250 also shows layer 1252 with semiconductor materialdeposited over barrier layer 1170. Layer 1252 could include vanadiumoxide (VO_(x)), heavily p-doped amorphous silicon, or other materialsuitable for low noise thermistors. Layer 1252 has been successfullyimplemented by sputtering VO_(x) over barrier layer 1170 underdeposition conditions that obtain required electrical and thermalcharacteristics and low compressive stress to prevent deformation andprovide flatness in layer 1162.

After layer 1252 has been deposited, an annealing operation improves lownoise characteristics. In particular, annealing in an appropriate gassuch as N₂ at a suitable temperature for an appropriate period of timedecreases resistivity of layer 1252 and reduces 1/f noise level of aresulting thermistor. Sheet resistance values on the order of 400KΩ/square have been obtained for a 300 nm thick film of VO_(x).

Additional information about techniques for producing layer 1252 andabout its characteristics and characteristics of other semiconductorlayers for low noise thermal sensors is set forth in co-pending U.S.patent application Ser. No. 11/______ [Attorney Docket No.A1578-US-CIP2/U1047/008], entitled “Resistive Thermal Sensing” andincorporated herein by reference in its entirety.

Cross-section 1260 illustrates a subsequent stage in which layer 1252has been patterned, such as by photolithographically producing anappropriate mask and then selectively removing layer 1252, leaving slab1230 as well as other components such as slabs 1232, 1234, and 1236(FIG. 14). Any suitable technique could be used, including wet etching,dry etching, or lift-off techniques. After patterning of layer 1252,conductive layer 1262 is deposited, such as by depositing a sandwich ofCr/Al/Cr or TiW/Al/Cr. If layer 1252 includes VO_(x), TiW/Al/Cr mayprovide better ohmic contact with VO_(x), improving noise performance.Lines, leads, and contact pads as shown in FIGS. 12 and 14, whenimplemented with materials such as these, can provide “low noise outputcircuitry”, a term used herein to refer to circuitry that, if connectedto one or more low noise thermal sensors such as low noise thermistors,provides an electrical output signal that includes no more thanapproximately twice the noise from the low noise thermal sensors. Inother words, low noise output circuitry would contribute no more noisethan would come from low noise thermal sensors to which it is connected.

Cross-section 1270 shows a subsequent stage at which layer 1262 has beenpatterned, such as by photolithographically producing a mask andperforming selective removal as described above. After patterning oflayer 1262, leads 1150 and 1152 extend across slab 1230 as well asaround it, while merger portions 1272 and 1274 of drop merger 1240 arealso produced. Other leads shown in FIG. 14 are also produced in thisstage, as well as the contact pads, all of which include conductivematerial from layer 1262.

Then, top layer 1276 is deposited, such as by depositing protectivelayers 1172 and 1174 (FIG. 13). As described above, layer 1172 providesan upper barrier layer. Openings to expose contact pads can be etchedthrough layer 1172, and a thin layer of TiAu or CrAu can then besputtered and patterned with the same mask, such as by a lift-offprocess, to provide improved ohmic contact on the surfaces of thecontact pads. On top of layer 1172, polymer layer 1174 is deposited,providing an additional barrier and a hydrophobic surface. Openings canthen be etched through layer 1174 to expose the thin layer of TiAu orCrAu on the contact pads. The entire structure on the surface of polymerlayer 1162 as shown in cross-section 1270 can be referred to as sensorstructure 1278.

Cross-section 1280 shows the other side of polymer layer 1162 on whichthermally conductive component 1160 has been formed. Cross-section 1280also illustrates the relationship of component 1160 to sensor structure1278, shown in profile on the other side of polymer layer 1162.

Component 1160 has been produced by depositing a 9 μm layer of copper,and then patterning it, such as by photolithographically forming a maskand performing selective removal as described above, producing thermallyconductive component 1160. In one implementation of this technique, thestarting substrate is a pre-manufactured structure that includes polymerlayer 1162 on which a layer of copper has been electrodeposited, such asby depositing one or more thin seed layers such as a chromium seed layerand a copper seed layer and then electroplating copper onto the seedlayers; in this implementation, the layer of copper can be selectivelyremoved at any appropriate point in the process to produce component1160. Techniques for producing such a starting substrate are describedin U.S. Pat. No. 4,863,808, incorporated herein by reference.

Anti-coupling coating 1164 is then deposited over component 1160. Theneed for anti-coupling coating 1164 may be reduced or eliminated,however, by using a pre-manufactured starting substrate as describedabove. More specifically, it may be possible to selectively remove anelectroplated copper layer and leave one or more seed layers intact, inwhich case the remaining seed layers may prevent capacitive coupling andthe resulting noise. In general, applicable anti-coupling measures aredescribed in greater detail in co-pending U.S. patent application Ser.No. 11/______ [Attorney Docket No. A1578-US-CIP4/U1047/012], entitled“Thermal Sensing” and incorporated herein by reference in its entirety.

After deposition of coating 1164, the resulting structure can be cut offof the frame on which it was mounted during processing and can beattached to frame 1202 (FIG. 14). Frame 1202 acts as a stiffener to holdlayer 1162 taut and flat. Further operations can be performed, such aslaser trimming of slabs 1142 and 1144 to balance bridge 1102.

When connected in circuit 1100 (FIG. 11), cell 1200 can be operated asfollows: Two drops of approximately 250 nl can be released on each ofdrop mergers 1240 and 1242. The drops on one merger can initiate areaction such as a protein-ligand binding reaction, an enzymaticreaction, or an organelle activity, while the drops on the other mergercan be non-reactive, providing a reference for differential measurement.After the drops reach thermal equilibrium, the drops on both mergers canbe concurrently merged and mixed by applying appropriate voltage signalsacross contact pads 1222 and 1224, as described in the Torres et al.article, incorporated by reference above.

A thermal input signal resulting from merging and mixing of drops isconducted downward through sensor structure 1278 and part of layer 1162to thermally conductive component 1160. Then, the thermal input signalis conducted laterally through component 1160 to the regions under slabs1230 and 1232, where they are conducted upward to slabs 1230 and 1232through part of layer 1162 and layer 1170. A change in temperature inthe slabs on one side of cell 1200 changes their resistance, resultingin detection of current through measuring thermistors 1110. Thecurrent's magnitude indicates the temperature difference betweenmeasuring thermistors 1110 and reference thermistors 1112.

FIG. 16 shows how an array of cells similar to cell 1200 (FIG. 14) canbe integrated on substrate 1300. As shown, array 1302 is 8 cells wide by12 cells long. To interface with standard automated laboratoryequipment, the cells are positioned on 9 mm centers and the automatedlaboratory equipment connects with the contact pads of each cell asdescribed above. Array 1302 can be one of several arrays fabricated on asingle substrate. Features of arrays and cells are also described inco-pending U.S. patent application Ser. No. 11/______ [Attorney DocketNo. A1578-US-CIP5/U1047/013], entitled “Thermal Sensing” andincorporated herein by reference in its entirety.

The implementations of FIGS. 12-16 include many features that are merelyillustrative and could be modified within the scope of the invention.For example, features could be included as described in the Torres etal. article, incorporated by reference above.

FIGS. 17-19 illustrate three modifications that could be made to theimplementations of FIGS. 12-16, in each case resulting in a cellstructure that could be used in the array of FIG. 16. Components thatare the same or have similar function as in FIG. 13 are labeled with thesame reference numerals.

In FIG. 17, the layer of conductive material that includes lines 1150,1152, 1154, and 1156 has been deposited and patterned before the layerof semiconductor material that includes slabs 1142 and 1144. Thisvariation is advantageous, for example, if fabrication is dividedbetween two entities, because it addresses a division of labor problem.More specifically, problems arise if one entity is required to workoutside its range of expertise or if a workpiece must be handed back andforth between the entities more than once. In the implementation of FIG.17, one entity could fabricate a preliminary set of components notincluding the semiconductor layer; after handoff, another entity withexpertise in semiconductor processing could then deposit and pattern thesemiconductor layer and then deposit one or more additional layers overthe components in the semiconductor layer to produce the finishedproduct. Such an approach can be advantageous, for example, where thedeposition or patterning of the semiconductor layer requires specializedexpertise that is not required for the conductive lines and othercomponents on polymer layer 1162.

Problems arise, however, in the variation of FIG. 17, because of poorelectrical contact between slabs 1142 and 1144 and lines 1150, 1152,1154, and 1156. These electrical contact problems may be caused by oneor more oxides formed on the metal conductive lines while thesemiconductor material was sputtered in an oxygen-rich plasmaenvironment. It was discovered, however, that the problems could besolved by using a suitable alloy of titanium and tungsten for theconductive lines, because the oxides produced during semiconductorsputtering are electrically conductive or semiconductive to an extentthat good electrical contact was formed. The titanium-tungsten lines canbe plasma cleaned before semiconductor sputtering to remove any oxideformed since they were produced. In general, the conductive lines couldinclude any metal, metal alloy, or other highly conductive material thatresults in good electrical contact formation.

The implementation of FIG. 17 thus illustrates an example of a devicethat includes a first layered structure with a support surface and asecond layered structure on the support surface. The second layeredstructure includes first and second sets of thermal sensor componentsand bridge circuitry electrically connecting the first and second setsin a bridge. Each thermal sensor component has electrical resistivitythat varies with temperature. Each of the first and second sets iscapable of receiving respective thermal signals and the thermal signalsreceived by the first set differ from those received by the second set.Each thermal sensor component has a lower surface disposed toward thesupport surface. The bridge circuitry is capable of receiving drivesignals to allow electrical detection of difference betweenresistivities of the first and second sets of thermal sensor components,and the difference indicates difference between the respective thermalsignals. The bridge circuitry includes, for each thermal sensorcomponent, at least two sets of one or more electrically conductiveportions that extend across and are in electrical contact with thethermal sensor component's lower surface.

The technique of producing the implementation of FIG. 17 illustrates amethod of producing a detecting device, where the detecting deviceincludes thermometer elements and bridge circuitry on a support layer.The method includes forming a patterned layer of conductive materialover a supporting surface of the support layer, and the patterned layerof conductive material includes part of the bridge circuitry. The methodalso includes forming a patterned layer of semiconductor material overthe part of the bridge circuitry. The patterned layer of semiconductormaterial includes the thermometer elements.

FIG. 18 shows a cross-section similar to that in FIGS. 13 and 17,illustrating a variation that could be applied either to theimplementation of FIG. 13 or to the implementation of FIG. 17. Ratherthan showing the specific layers on polymer layer 1162, FIG. 18 simplyshows schematically a pair of control/sensor elements 1310 within ageneral layer 1312. General layer 1312 can include several sublayerssuch as layers 1172 and 1174 in FIGS. 13 and 17 or other sublayers; thesublayers of general layer 1312 can perform various functions, byproviding, for example, passivation, insulation, a hydrophobic oroleophobic top surface 1320, and so forth.

In this variation, elements 1314 and 1316 function both as components ofthermal sensors and also as electrodes to control drop merging. In otherwords, in addition to the signals they may receive during detection ofvoltage across a bridge, elements 1314 and 1316 receive drop mergesignals, such as a high voltage pulse with opposite polarity through thesame conductive lines described above in relation to FIGS. 12-15 and 17.The circuitry connected to the conductive lines through the contact padsmust therefore include appropriate protection for amplifier circuitry,such as a switch or other component to decouple the amps during the highvoltage pulse, or some other circuitry to protect against electrostaticdamage.

FIG. 18 illustratively shows protein drop 1330 and ligand drop 1332,both deposited on top surface 1320 of general layer 1312. Protein drop1330 is deposited asymmetrically over the gap between elements 1314 and1316 with a larger proportion of drop 1330 directly above element 1316than the proportion above element 1314. Ligand drop 1332, on the otherhand, is entirely above element 1314.

Signal source 1334 provides a high voltage pulse across elements 1314and 1316. As described above in relation to FIG. 6, this causes drop1330 to be propelled leftward toward stationary ligand drop 1332,causing the two drops to merge and mix.

The variation in FIG. 18 can be advantageous because separate dropmerger electrodes are unnecessary, making it possible to increase thesize of elements 1314 and 1316 as well as the other components in thethermal sensors and bridge circuitry without increasing the size of thecell. For example, semiconductor slabs with larger lengths and widthscould be produced with the same resistance, such as by depositing athinner layer of semiconductor material, a layer of semiconductormaterial with greater conductivity, or by patterning the conductivelines to have different spacings. As slab dimensions increase, smalldifferences in slab length or width are proportionally smaller relativeto total length or width; for example, if the fabrication technologyallows a given width+0.5 μm, an increase in width from 100 to 500 μmreduces the percentage of error from 0.5% to 0.1%, which would assist inachieving a design goal of keeping a bridge's offset voltage below 0.1%.Therefore, the offset voltage of a bridge can be more easily reduced bymaking the slab sizes approximately equal.

The same advantage applies to the variation shown in FIG. 19, but it hasthe additional advantage that thermally conductive component 1160 hasbeen omitted, making anti-coupling layer 1164 unnecessary. As a result,polymer layer 1162 can be somewhat thicker, as shown. For example,polymer layer 1162 could be a thicker layer of Kapton® or anotherpolyimide layer. A significant advantage of using a thicker polymerlayer is that fabrication is easier because there is less risk oftearing the polymer during handling. In other respects, the variation ofFIG. 19 can be the same as FIG. 18, as described above.

The implementations of FIGS. 12-19 illustrate examples of devices, eachof which includes a support layer. Two or more resistive thermometerelements are on the support layer, together with bridge circuitry. Thebridge circuitry electrically connects first and second subsets of thethermometer elements in a bridge, and the bridge circuitry has one ormore detection points. The bridge circuitry is capable of being drivento allow electrical detection, at the detection points, of differencesbetween first and second temperature changes. The first temperaturechange is received by the first subset of the thermometer elements andthe second temperature change is received by the second subset of thethermometer elements.

The technique of FIG. 15 and its modifications to produce structures asin FIGS. 17-19 illustrate examples of methods of producing detectingdevices. The methods include producing resistive thermometer elementsand bridge circuitry as described above. In particular, the thermometerelements and the bridge circuitry are produced on a support layer.

The array of FIG. 16, including cells implemented with detectors as inany of FIGS. 12-15, 17, 18, or 19, illustrates an example of an arraywith a support layer and not less than one detector on the supportlayer. Each detector includes two or more resistive thermometer elementson the support layer, together with bridge circuitry. The bridgecircuitry electrically connects first and second subsets of thethermometer elements in a bridge, and the bridge circuitry has one ormore detection points. The bridge circuitry is capable of being drivento allow electrical detection, at the detection points, of differencesbetween first and second temperature changes. The first temperaturechange is received by the first subset of the thermometer elements andthe second temperature change is received by the second subset of thethermometer elements.

The implementations of FIGS. 18 and 19 also illustrate examples ofdevices as described above in which the thermally isolated regions thatinclude the first and second subsets of thermometer elements alsoinclude reaction surfaces. A reaction can occur on one of the reactionsurfaces, producing reaction thermal change. The reaction surface isover the respective subset of thermometer elements, so that thetemperature change received by the thermometer elements includesreaction thermal change from the reaction surface. The device alsoincludes, below the reaction surface, a component that mixes fluids onthe reaction surface, such as drop merging electrodes.

FIG. 20 illustrates general operations in performing calorimetry or asimilar application of an array as in FIG. 16 with cells as describedabove in relation to FIGS. 12-15, 17, 18, or 19. In box 1350, drops aredeposited on the surfaces of the measurement and reference sides of aset of cells in an array, with the drops being appropriately positionedover drop merging electrodes as described above. In box 1352, the arrayis transferred into a measurement position, and electrical contacts aremade, such as with pogo pins being extended against contact pads of thearray. Then, in box 1354, drop merging pulses are providedsimultaneously to both sides of one or more cells, and the bridgecircuitry of those cells is also driven to allow electrical detection ofthe difference between thermal signals received at the measurement andreference sides of each cell. As suggested by the dashed line around box1354, the operation can be repeated as appropriate for any subset of thecells on which drops were deposited in box 1350; for example, the cellscould be read out one by one, or other appropriate subsets could be readout, up to the case in which all cells are read out in parallel whichmay be possible if noise and intercell interference can be adequatelycontrolled.

In the implementations described above, bridges illustratively have oneterminal receiving an AC drive voltage and another connected to ground,but the same terminals could receive any other appropriate combinationof voltages. For example, the terminal connected to ground could insteadbe connected to some other voltage different than the AC drive voltage,or the bridge could be driven by a balance transformer in which case theterminals are driven with opposite polarities relative to ground. Any ofthese variations would be within the scope of box 1354 in FIG. 20.

The technique of FIG. 20 illustrates another example of a method ofusing a device as described above. The method includes depositing dropsof fluid on a reaction surface and a reference surface. The method alsoincludes simultaneously activating drop merging electrodes in theregions that include the reaction surface and the reference surface tocause simultaneous reactions on the surfaces.

More generally, the implementations of FIGS. 12-20 are advantageousbecause they permit high sensitivity and high throughput in a label freecalorimetric detection system, such as in proteomic and drug developmentresearch. Sensitivities as fine as single-digit microdegree resolutionor better can be achieved, and the noise level of thermistors asdescribed can approach the Johnson noise level. At the same time, othermaterial properties that affect resolution are preserved, such as highTCR, thus improving the overall signal-to-noise ratio of an instrument.As a result, the array of FIG. 16 can advantageously be implemented tomeasure thermal change from merged drops with single digit micromolarconcentrations of molecules.

The techniques described above are useful for calorimetry measurements,such as in biophysical and biochemical studies to determine energychanges as indications of biochemical reactions. Calorimetrymeasurements are useful in a broad variety of applications, including,for example, pharmaceuticals (drug discovery, decomposition reactions,crystallization measurements), biology (cell metabolism, druginteractions, fermentation, photosynthesis), catalysts (biological,organic, or inorganic), electrochemical reactions (such as in batteriesor fuel cells), polymer synthesis and characterization, and so forth. Ingeneral, calorimetry measurements can be useful in the discovery anddevelopment of new chemicals and materials of many types, as well as inthe monitoring of chemical processes.

In addition to calorimetry applications, techniques described above maybe used in various other thermal sensing applications.

Some of the above exemplary implementations involve specific materials,such as amorphous silicon or vanadium oxide in thermistors; any ofvarious polymers in a supporting layer; copper, aluminum, chromium, TiW,or a combination of them in conductive components; silicon oxynitride inbarrier layers; and so forth, but the invention could be implementedwith a wide variety of materials and with layered structures withvarious combinations of sublayers. In particular, other substratematerials such as silicon or other types of support structures could beused besides those specified above, and a wide variety of materialscould be used in device layers, insulating layers, leads, lines,electrodes, and other components; for example, a top coating of sputterdeposited SiO_(x) or PECVD SiO or SiN could be provided. In addition,components could have various shapes, dimensions, or other numerical orqualitative characteristics other than those illustrated and describedabove.

Some of the above exemplary implementations involve two-dimensionalarrays of thermal sensor cells with specified circuitry includingcircuitry connecting sensors as in a Wheatstone bridge and with a dropmerging component, but the invention could be implemented with a singlecell or with a one-dimensional array and with any suitable thermalsensor circuitry, with or without a drop merger and with sensorsconnected as in any appropriate type of bridge. In the above exemplaryimplementations, certain parts of a bridge take the form of bridgecircuitry on the same support layer or surface as thermal sensors, butmore or fewer components of the bridge could be on the same supportlayer or surface with the sensors. The above exemplary implementationsgenerally involve cells with particular circuitry for other power andsignal functions, but various other arrangements could be used.

The above exemplary implementations generally involve production and useof thermal sensors, devices, cells, and arrays following particularoperations, but different operations could be performed, the order ofthe operations could be modified, and additional operations could beadded within the scope of the invention. For example, as noted above,conductive lines could be formed before or after semiconductor slabs.Also, the positioning of components on the sides of a polymer layer orother support structure could be modified within the scope of theinvention. During use, electrical signals could be provided tocomponents in any appropriate sequence.

While the invention has been described in conjunction with specificexemplary implementations, it is evident to those skilled in the artthat many other alternatives, modifications, and variations will beapparent in light of the foregoing description. Accordingly, theinvention is intended to embrace all other such alternatives,modifications, and variations that fall within the spirit and scope ofthe appended claims.

1. A device comprising: a support layer; on the support layer: two ormore resistive thermometer elements; and bridge circuitry electricallyconnecting first and second subsets of the thermometer elements in abridge, each subset including one or more of the thermometer elements;the bridge circuitry having a set of one or more detection points; thebridge circuitry being capable of being driven to allow electricaldetection, at the detection points, of difference between first andsecond temperature changes, the first temperature change being receivedby the first subset of the thermometer elements and the secondtemperature change being received by the second subset of thethermometer elements.
 2. The device of claim 1 in which the supportlayer includes first and second regions that are substantially thermallyisolated from each other, the first subset of the thermometer elementsbeing on the first region and the second subset of the thermometerelements being on the second region; the device further comprising: onthe first region, a first thermally conductive structure having thermalcontact with each of the first subset of the thermometer elements; andon the second region, a second thermally conductive structure havingthermal contact with each of the second subset of the thermometerelements.
 3. The device of claim 2 in which the support layer has firstand second sides opposite each other; the first and second subsets ofthermometer elements and the bridge circuitry being on the first side;the first and second thermally conductive structures being on the secondside.
 4. The device of claim 2, further comprising: on the first region,a reaction surface on which reactions occur, producing reaction thermalchange; the first thermally conductive structure being in thermalcontact with the reaction surface; the first temperature changeincluding reaction thermal change from the reaction surface.
 5. Thedevice of claim 4, further comprising: on the first region, a componentthat mixes fluids on the reaction surface; the reaction thermal changeincluding heat of reaction between mixed fluids.
 6. The device of claim4 in which the second temperature change includes reference temperaturechange, the difference between the first and second temperature changesindicating difference between the reaction thermal change from thereaction surface and the reference temperature change.
 7. The device ofclaim 6, further comprising: on the second region, a reference surfaceexposed to the reference temperature change; the second thermallyconductive structure being in thermal contact with the referencesurface.
 8. The device of claim 7, further comprising: on the secondregion, drop merging electrodes that mix fluids on the referencesurface.
 9. A method of using the device of claim 8, comprising:depositing drops of fluids on the reaction surface and the referencesurface; and simultaneously activating the drop merging electrodes inthe first and second regions to cause simultaneous reactions on thereaction surface and the reference surface.
 10. The device of claim 8,further comprising reaction control lines connected to the drop mergingelectrodes in the first and second regions; the reaction control linesbeing connected so that the drop merging electrodes in the first andsecond regions are simultaneously activated.
 11. The device of claim 2in which the first and second subsets of the thermometer elements are onleft and right sides, respectively, of a symmetry axis extending acrossthe support layer between the first and second regions; the first andsecond subsets being substantially symmetrical with respect to eachother about the symmetry axis; the first and second thermally conductivestructures being on the left and right sides, respectively, of thesymmetry axis and being substantially symmetrical with respect to eachother about the symmetry axis.
 12. The device of claim 1 in which thesupport layer includes first and second regions that are substantiallythermally isolated from each other, the first subset of the thermometerelements being on the first region and the second subset of thethermometer elements being on the second region; the device furthercomprising: on the first region, a reaction surface on which reactionsoccur, producing reaction thermal change; the reaction surface beingover the first subset of thermometer elements, the first temperaturechange including reaction thermal change from the reaction surface. 13.The device of claim 12, further comprising: on the first region, belowthe reaction surface, a component that mixes fluids on the reactionsurface; the reaction thermal change including heat of reaction betweenmixed fluids.
 14. The device of claim 13 in which the component thatmixes fluids includes drop merging electrodes.
 15. The device of claim 1in which the bridge's offset voltage is below the sensitivity limit foran application.
 16. The device of claim 15 in which the thermometerelements are patterned from a first layer of material and the bridgecircuitry includes a part patterned from a second layer of material; thefirst and second subsets of thermometer elements and the part of thebridge circuitry being shaped and positioned so that the bridge's offsetvoltage is below the sensitivity limit despite process variations inpatterning the first and second layers of material.
 17. A devicecomprising: a first layered structure with a support surface; and asecond layered structure on the support surface, the second layeredstructure including: first and second sets of thermal sensor components,each thermal sensor component having electrical resistivity that varieswith temperature; the first set and second set each being capable ofreceiving respective thermal signals, with thermal signals received bythe first set differing from thermal signals received by the second set;each thermal sensor component having a lower surface disposed toward thesupport surface; and bridge circuitry electrically connecting the firstand second sets of thermal sensor components in a bridge; the bridgecircuitry being capable of receiving drive signals to allow electricaldetection of difference between resistivities of the first and secondsets of thermal sensor components, the difference in resistivitiesindicating difference between respective thermal signals received by thefirst and second sets of thermal sensor components; the bridge circuitryincluding: for each thermal sensor component, at least two sets of oneor more electrically conductive portions extending across and inelectrical contact with the thermal sensor component's lower surface.18. The device of claim 17 in which the first layered structure includesa layer of polymer material.
 19. The device of claim 17 in which each ofthe first and second sets of thermal sensor components is a pair ofthermal sensor components.
 20. The device of claim 17 in which the setsof conductive portions for each thermal sensor component include firstand second sets, the conductive portions in the first set beingelectrically connected to each other on a first side of the thermalsensor component and the conductive portions in the second set beingelectrically connected to each other on a second side of the thermalsensor component opposite the first side; the first and second sets ofconductive portions being interdigitated.
 21. The device of claim 17 inwhich the conductive portions are formed from a first layer of materialdeposited over the support surface and the thermal sensor components areformed over the conductive portions.
 22. The device of claim 17 in whichthe thermal sensor components include semiconductor material.
 23. Thedevice of claim 22 in which the conductive portions include a conductivematerial that has a conductive or semiconductive surface oxide layerproviding electrical contact with the semiconductor material in thethermal sensor components.
 24. The device of claim 23 in which theconductive material is an alloy of titanium and tungsten.
 25. An arraycomprising: a support layer; not less than one detector on the supportlayer, each detector including: two or more resistive thermometerelements; and bridge circuitry electrically connecting first and secondsubsets of the thermometer elements in a bridge, each subset includingone or more of the thermometer elements; the bridge circuitry having aset of one or more detection points; the bridge circuitry being capableof being driven to allow electrical detection, at the detection points,of difference between first and second temperature changes, the firsttemperature change being received by the first subset of the thermometerelements and the second temperature change being received by the secondsubset of the thermometer elements.
 26. The array of claim 25 in whicheach thermometer element includes a semiconductor component with a lowersurface disposed toward the support layer; the bridge circuitryincluding at least two sets of one or more electrically conductiveportions extending across and in electrical contact with thesemiconductor component's lower surface.
 27. A method of producing adetecting device, the method comprising: producing two or more resistivethermometer elements and bridge circuitry electrically connecting firstand second subsets of the thermometer elements in a bridge, each subsetincluding one or more of the thermometer elements; the bridge circuitryhaving a set of one or more detection points; the bridge circuitry beingcapable of being driven to allow electrical detection, at the detectionpoints, of difference between first and second temperature changes, thefirst temperature change being received by the first subset of thethermometer elements and the second temperature change being received bythe second subset of the thermometer elements; the act of producing thethermometer elements and the bridge circuitry comprising: producing thethermometer elements and the bridge circuitry on a support layer. 28.The method of claim 27 in which the support layer has a supportingsurface; the act of producing the thermometer elements and the bridgecircuitry on the support layer comprising: forming a patterned layer ofconductive material over the supporting surface; the patterned layer ofconductive material including part of the bridge circuitry; and forminga patterned layer of semiconductor material over the part of the bridgecircuitry; the patterned layer of semiconductor material including thethermometer elements.